Compositions and methods for adjoining type I and type II extracellular domains as heterologous chimeric proteins

ABSTRACT

The present invention relates to, inter alia, compositions and methods, including chimeric proteins that find use in the treatment of disease, such as immunotherapies for cancer and autoimmunity. In part, the invention provides, in various embodiments, fusions of extracellular domains of transmembrane proteins that can have stimulatory or inhibitory effects.

PRIORITY

This application is a continuation of U.S. application Ser. No. 15/281,196, filed Sep. 30, 2016. U.S. Ser. No. 15/281,196 claims the benefit of, and priority to, U.S. Provisional Application No. 62/235,727, filed Oct. 1, 2015, U.S. Provisional Application No. 62/263,313, filed Dec. 4, 2015, and U.S. Provisional Application No. 62/372,574, filed Aug. 9, 2016. The contents of each above-mentioned application are hereby incorporated by reference in their entireties.

TECHNICAL FIELD

The present invention relates to, inter alia, compositions and methods, including chimeric proteins that find use in the treatment of disease, such as immunotherapies for cancer and autoimmunity.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: SHK-HTB-023C1_SequenceListing_ST25; date recorded: Nov. 6, 2017; file size: 139 KB).

BACKGROUND

The interaction between cancer and the immune system is complex and multifaceted. See de Visser et al., Nat. Rev. Cancer (2006) 6:24-37. While many cancer patients appear to develop an anti-tumor immune response, cancers also develop strategies to evade immune detection and destruction. Recently, immunotherapies have been developed for the treatment and prevention of cancer and other disorders. Immunotherapy provides the advantage of cell specificity that other treatment modalities lack. As such, methods for enhancing the efficacy of immune based therapies can be clinically beneficial. Advances in defining the mechanisms and molecules that regulate immune responses have provided novel therapeutic targets for treating cancer. For example, costimulatory and coinhibitory molecules play a central role in the regulation of T cell immune responses. However, despite impressive patient responses to antibody agents targeting these costimulatory and coinhibitory molecules, including for example anti-PD-1/PD-L1, checkpoint inhibition therapy still fails in many patients. Therefore, as with most cancer therapies, there remains a need for new compositions and methods that can improve the effectiveness of these agents.

SUMMARY

Accordingly, in various aspects, the present invention provides for compositions and methods that are useful for cancer immunotherapy, e.g. to manipulate or modify immune signals for therapeutic benefit. In various embodiments, the invention reverses or suppresses immune inhibitory signals while providing immune activating or co-stimulatory signals in a beneficial context. For instance, in one aspect, the present invention provides chimeric protein comprising: (a) a first extracellular domain of a type I transmembrane protein at or near the N-terminus, (b) a second extracellular domain of a type II transmembrane protein at or near the C-terminus, and (c) a linker, wherein one of the first and second extracellular domains is an immune inhibitory signal and one of the first and second extracellular domains is an immune stimulatory signal. By linking these two molecules in a functional orientation, coordination between the positive and negative signals can be achieved. For example, the present invention provides, in various embodiments, masking of negative immune signals and stimulation of positive immune signals in a single construct. In various embodiments, provides for compositions that are not antibodies, or based upon antibody-derived antigen binding domains (e.g. complementarity determining regions, CDRs), but rather provide direct receptor/ligand interaction.

In cancer patients, an immune response can be stimulated against tumor antigens to activate a patient's own immune system to kill tumor cells. However, some cancer cells devise strategies to evade an immune response in a process known as immuno-editing. This can include down-regulation of specific antigens, down-regulation of MHC I, up-regulation of immune regulatory surface molecules (PD-L1, PD-L2, CEACAM1, galectin-9, B7-H3, B7-H4, VISTA, CD47, etc.) or up-regulation of soluble immune inhibitory molecules (IDO, TGF-β, MICA, etc). In general, these strategies are co-opted by tumor cells so that when tumor-infiltrating immune killer cells encounter a tumor cell, those cells become directly inhibited by immunosuppressive factors and therefore cannot kill the tumor cell. Many of the immunosuppressive ligands co-opted by tumor cells to suppress an immune response interact with receptors that are type I membrane proteins. In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of an immune inhibitory agent, including without limitation, one or more of TIM-3, BTLA, PD-1, CTLA-4, B7-H4, PD-L1, PD-L2, B7-H3, CD244, TIGIT, CD172a/SIRPα, VISTA/VSIG8, CD115, CD200, CD223, and TMIGD2. In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of a type I membrane protein which has immune inhibitory properties. In various embodiments, the chimeric protein is engineered to disrupt, block, reduce, and/or inhibit the transmission of an immune inhibitory signal, by way of non-limiting example, the binding of PD-1 with PD-L1 or PD-L2 and/or the binding of CD172a with CD47 and/or the binding of TIM-3 with one or more of galectin-9 and/or phosphatidylserine.

Further, in addition to suppression of immune inhibitory signaling, it is often desirable to enhance immune stimulatory signal transmission to boost an immune response, for instance to enhance a patient's anti-tumor immune response. In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of an immune stimulatory signal, which, without limitation, is one or more of OX-40 ligand, LIGHT (CD258), GITR ligand, CD70, CD30 ligand, CD40 ligand, CD137 ligand, TRAIL and TL1A. In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of a type II membrane protein which has immune stimulatory properties. In various embodiments, the chimeric protein is engineered to enhance, increase, and/or stimulate the transmission of an immune stimulatory signal, by way of non-limiting example, the binding of GITR with one or more of GITR ligand and/or the binding of OX40 with OX40L and/or CD40 with CD40 ligand.

In various embodiments, the chimeric protein comprises an immune inhibitory receptor extracellular domain and an immune stimulatory ligand extracellular domain which can, without limitation, deliver an immune stimulation to a T cell while masking a tumor cell's immune inhibitory signals. In various embodiments, the present chimeric proteins provide improved immunotherapeutic benefits by effectively causing the substitution of an immune inhibitory signal for an immune stimulatory signal. For example, a chimeric protein construct comprising (i) the extracellular domain of PD-1 and (ii) extracellular domain of OX40L, allows for the disruption of an inhibitory PD-L1/L2 signal and its replacement with a stimulating OX40L. Accordingly, the present chimeric proteins, in some embodiments are capable of, or find use in methods involving, reducing or eliminating an inhibitory immune signal and/or increasing or activating an immune stimulatory signal. Such beneficial properties are enhanced by the single construct approach of the present chimeric proteins. For instance, the signal replacement can be effected nearly simultaneously and the signal replacement is tailored to be local at a site of clinical importance (e.g. the tumor microenvironment). Further embodiments apply the same principle to other chimeric protein constructs, such as, for example, (i) the extracellular domain of PD-1 and (ii) extracellular domain of GITRL; (i) the extracellular domain of BTLA and (ii) extracellular domain of OX40L; (i) the extracellular domain of TIGIT and (ii) extracellular domain of OX40L; (i) the extracellular domain of TMIGD2 and (ii) extracellular domain of OX40L; (i) the extracellular domain of TIM3 and (ii) extracellular domain of OX40L; and (i) the extracellular domain of CD172a or CD115 and (ii) extracellular domain of CD40L; among others.

Further still, in some embodiments, the present chimeric proteins are capable of, or find use in methods involving, shifting the balance of immune cells in favor of immune attack of a tumor. For instance, the present chimeric proteins can shift the ratio of immune cells at a site of clinical importance in favor of cells that can kill a tumor (e.g. T cells, cytotoxic T lymphocytes, T helper cells, natural killer (NK) cells, natural killer T (NKT) cells, anti-tumor macrophages (e.g. M1 macrophages), B cells, and dendritic cells and in opposition to cells that protect tumors (e.g. myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs); tumor associated neutrophils (TANs), M2 macrophages, and tumor associated macrophages (TAMs)). In some embodiments, the present chimeric protein is capable of increasing a ratio of effector T cells to regulatory T cells.

In various embodiments, the present chimeric protein unexpectedly provides binding of the extracellular domain components to their respective binding partners with longer off rates (Kd or K_(off)) and therefore, inter alia, accords longer occupancy of the receptor to ligand and vice versa. For instance, in some embodiments, this provides a sustained negative signal masking effect. Further, in some embodiments, this delivers a longer positive signal effect, e.g. to allow an effector cell to be adequately stimulated (e.g. for proliferation and/or release of stimulatory signals like cytokines). Also, this stable synapse of cells (e.g. a tumor cell bearing negative signals and a T cell which could attack the tumor) provides spatial orientation to favor tumor reduction—such as positioning the T cells to attack tumor cells and/or sterically preventing the tumor cell from delivering negative signals, including negative signals beyond those masked by the chimeric protein of the invention. In still further embodiments, this provides longer on-target (e.g. intra-tumoral) half-life (t_(1/2)) as compared to serum t_(1/2) of the chimeric proteins. Such properties could have the combined advantage of reducing off-target toxicities associated with systemic distribution of the chimeric proteins.

Also in various aspects, the present chimeric protein is used in a method for treating cancer comprising administering an effective amount of a pharmaceutical composition comprising the chimeric protein to a patient in need thereof. In further aspects, the present chimeric protein is used in a method for treating infections, including without limitation, viral infections or other intracellular pathogens. In still further aspects, the present chimeric protein is used in a method for treating autoimmune diseases.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows illustrations of orientations of type I (left) and type II (right) membrane proteins in a cell membrane. In the type I membrane protein of the left panel, the amino terminus (denoted “N”) faces the extracellular environment and the carboxy terminus (denoted “C”) is localized to the intracellular environment. In contrast, the type II membrane protein of the right panel is characterized by an extracellular facing carboxy terminus and an amino terminus in the intracellular space.

FIG. 2 shows immune inhibitory and immune stimulatory signaling that is relevant to the present invention (from Mahoney, Nature Reviews Drug Discovery 2015:14; 561-585).

FIG. 3 shows a schematic illustration of how a type I and type II membrane protein (panel A) may be engineered with transmembrane and intracellular domains removed (panel B) and adjoined using a linker sequence (panel C) to generate a single fusion protein wherein the extracellular domains of the type I and type II membrane proteins each face outward in a single fusion protein (panel D). Panel C depicts the linkage of a type I and type II membrane protein by removal of the transmembrane and intracellular domains of each protein, and where the liberated extracellular domains (ECD) from each protein have been adjoined by a linker sequence. The ECD in this depiction may include the entire amino acid sequence of a candidate type I or type II protein which is typically localized outside the cell membrane, or any portion thereof which retains binding to the intended receptor or ligand. Panel D depicts adjoined extracellular domains in a linear construct wherein the extracellular domain of the type I membrane protein faces the ‘left’ side of the construct and the extracellular domain of the type II membrane protein faces the “right” side of the construct.

FIG. 4 shows that tumor cells may express PD-L1 on the cell surface (panel A), which can bind to PD-1 expressed by a T cell (panel B). This interaction suppresses activation of T cells. A fusion protein of the extracellular domain of PD-1, adjoined to the extracellular domain of OX40L may bind to PD-L1 on the surface of a tumor cell, preventing binding to PD-1 on the surface of a T cell (panel C). The fusion protein may then ‘dangle’ from the surface of the tumor cell, and the OX40L portion of the fusion protein may then bind to OX40 expressed on the surface of the T cell. This would result in replacement of an inhibitory PD-L1 signal with a co-stimulatory OX40L signal to enhance the anti-tumor activity of T cells.

FIG. 5 shows the expression of chimeric mouse (m) PD-1-Fc and PD-1-Fc-OX40 ligand (L) from CHO-K1 cells detected using a mouse IgG capture and anti-mIgG detection ELISA assay.

FIG. 6 shows results from an ELISA assay confirming the binding of mPD-1-Fc-OX40L to mOX40. Panel A shows a schematic representation of the ELISA method used to detect binding of mPD-1-Fc-OX40L to mOX40. Recombinant mOX40 fused to human Fc (mOX40-hFc) was used to capture mPD-1-Fc-OX40L in the culture media. A rabbit polyclonal antibody to mPD-1 was used to detect the mPD-1 domain in the chimeric protein and subsequently detected using a horseradish peroxidase (HRP)-conjugated polyclonal antibody to rabbit IgG (H+L). Panel B shows results in which two-fold serial dilutions of the CHO-K1 culture media containing mPD-1-Fc-OX40L protein was incubated with plate-bound mOX40-hFc and binding was measured by absorbance at 450 nm. mPD-1-Fc protein (which is not predicted to bind recombinant mouse OX40) containing culture media, as well as culture media alone, were used as negative controls.

FIG. 7 shows results from an ELISA assay confirming binding of mPD-1-Fc-OX40L to mPD-L1. Panel A shows a schematic representation of the ELISA method used to detect binding of mPD-1-Fc-OX40L to mPD-L1. Recombinant mPD-L1 fused to human Fc (mPD-L1-hFc) was used to capture the mPD-1-Fc-OX40L chimeric protein in the culture media. A horseradish peroxidase (HRP)-conjugated polyclonal antibody to mouse IgG (H+L) was used for the detection of the bound proteins. Panel B shows results in which two-fold serial dilutions of CHO-K1 culture media containing mPD-1-Fc-OX40L protein was incubated with plate-bound mPD-L1-hFc and binding was measured by absorbance at 450 nm. mPD-1-Fc protein containing culture media was used as a positive control and media alone was used as a negative control.

FIG. 8 shows that the in vivo intratumoral delivery of plasmid DNA encoding mouse (m) PD-1-Fc-OX40L led to an expansion of antigen-specific CD8+ T-cells. “EP only” is an electroporation negative control. In this experiment, C57BL/6 mice were adoptively transferred with ovalbumin-specific CD8+ T cells (OT-I) 2 days before tumor inoculation. B16-F10-ova tumors were then implanted on the hind flank of each mouse on day 0. 7-day established B16-F10-ova tumors were injected with the plasmid DNA encoding mPD1-Fc-OX40L and electroporated immediately thereafter on days 7 and 10, as compared to the EP only control. The frequency of OT-I cells was measured on the indicated days in the peripheral blood by flow cytometry.

FIG. 9 shows that the in vivo intratumoral delivery of plasmid DNA encoding mPD-1-Fc-OX40L led to tumor regression in the B16.F10-ova melanoma tumor model. “EP only” is an electroporation negative control. Mice were treated as indicated in FIG. 9, and the tumor diameter was measured on the indicated days.

FIG. 10 shows results from additional characterization of mPD-1-Fc-OX40L. Panel A provides Western blot analysis probed with antibodies for mPD-1 (left gel), mFc (middle panel) and mOX40L (right panel), run in reducing or non-reducing condition and with or without the deglycosylase PNGase F (as indicated by the ‘+’ or ‘−’ marks above each blot). The murine protein has a predicted molecular weight of ˜60 kDa as a monomeric protein. Panel B shows results from a functional ELISA assay demonstrating the binding of mPD-1-Fc-OX40L to mPD-L1 and mOX40. For each set of histograms, the bars represent, from left to right, a serial dilution of the purified mPD1-Fc-OX40L fusion protein. Panel C shows results from a functional ELISA assay demonstrating the binding of mPD-1-Fc-OX40L to mFc (for each concentration, OX40-His is the left bar and HVEM-His is the right bar). Panel D shows binding to mPD-1-Fc-OX40L to activated mouse splenocytes as detected on HLA I-A/I-E⁺PD-L1⁺ (APC⁺PD-L1⁺) and CD4⁺OX40⁺ cells (for each graph, the cell populations to the left represent APC⁻PD-L1⁻ or CD4⁻OX40⁻ cells and the cell populations to the right represent APC⁺PD-L1⁺ or CD4⁺OX40⁺ cells). Panel E shows identification of PD-L1_(low) (4T1) and PD-L1_(high) (B16.F10) cell lines. Panel F shows results from a splenocyte/tumor co-culture assay. IL2 ELISA was performed 5 days after initial harvest. The line graphs from left to right represent +4T1 cells (−FP), +4T1 cells (+500 ng FP), +4T1 cells (+5 ug FP), +B16 cells (−FP), +B16 cells (+500 ng FP), and +B16 cells (+5 ug FP).

FIG. 11 shows the anti-tumor efficacy of mPD-1-Fc-OX40L. Panel A shows MC38 tumor growth kinetics following treatment with the indicated regimens. Balb.c mice were inoculated in the hind flank with 2.5×10⁵ MC38-ova tumor cells. On days 5 and 8, mice were treated with the indicated treatment group. Anti-OX40 treated animals received 100 μg of OX86 mAb on each of two days, anti-PD-L1 treated animals received 100 μg of 10F.9G2 mAb on each of two days, anti-OX40 and anti-PD-L1 combination treated animals received 100 μg each of OX86 and 10F.9G2 on each of two days and mPD1-Fc-OX40L treated mice received 100 μg total of mPD1-Fc-OX40L on each of two days. Tumor area was calculated on the indicated days by taking perpendicular tumor diameter measurements using electronic calipers. On day 40, mice which had completely rejected the prior tumor (no visible or palpable tumor remained), were challenged with 2.5×10⁵ MC38 parental (not expressing ova) tumor cells, without any additional treatment, and tumor area was calculated as stated above. Panel B shows the overall survival for each treatment group over the course of the experiment as determined by overall tumor size exceeding 150 mm² according to IACUC protocols (at day 65, the curves are, top to bottom, αOX40/αPD-L1, mPD1-Fc-OX40L, αOX40, αPD-L1, and untreated). Panel C shows peripheral blood analysis of CD4/CD8 ratio (top) and the percentage of FOXP3+ Treg cells (bottom) for each indicated treatment group (in both graphs, the treatment groups are, left to right, untreated, αOX40, αPD-L1, αOX40/αPD-L1, and mPD1-Fc-OX40L). Panel D shows serum cytokine analysis of IFNγ, TNFα, IL4, and IL6. For each set of data, the line graphs from left to right represent untreated, α-OX40, α-PD-L1, α-OX40/α-PD-L1, and mPD-1-Fc-OX40L (in the four graphs, the treatment groups are, left to right, untreated, αOX40, αPD-L1, αOX40/αPD-L1, and mPD1-Fc-OX40L). Panel E shows the mean tumor size for each treatment group on day 13 of the experiment (for each graph, the samples are, left to right: untreated, mPD1-Fc-OX40L, mPD1-Fc-GITRL, mCD172a-Fc-CD40L, αOX40, αPD-L1, and α GITR). Panel F shows the percentage of KSP Tetramer specific CD8+ T cells isolated from the tumor (TIL) for each treatment group on day 13 of the experiment (for each graph, the samples are, left to right: untreated, mPD1-Fc-OX40L, mPD1-Fc-GITRL, mCD172a-Fc-CD40L, αOX40, αPD-L1, and a GITR). Panel G shows the phenotype of CD8+ splenocytes according to well characterized ‘immune memory’ markers on day 13 of the experiment for each treatment group (for each graph, the samples are, left to right: untreated, mPD1-Fc-OX40L, mPD1-Fc-GITRL, mCD172a-Fc-CD40L, αOX40, αPD-L1, and a GITR). Panel H shows the ratio of CD4 to CD8 cells in the peripheral blood (left panel), spleen (middle panel) and tumor (right panel) for each treatment group on day 13 of the experiment (for each graph, the samples are, left to right: untreated, mPD1-Fc-OX40L, mPD1-Fc-GITRL, mCD172a-Fc-CD40L, αOX40, αPD-L1, and α GITR). Panel I shows a schematic for how each animal was treated in each experiment using the CT26 colon tumor model. Panel J provides representative flow cytometry plots used to calculate the serum concentration of each indicated serum cytokine using the Legend Plex bead array kit from BioLegend. Each indicated cytokine included in the panel is indicated, and the mean-fluorescence intensity of each bead cluster is used to calculate the relative concentration of each cytokine in the serum. Panel K provides an example for how the Legend Plex assay can be used as a pharmacodynamic biomarker of dose response for the PD1-Fc-OX40L fusion protein. Using the concentration of IFNγ as an example, increasing concentrations of this cytokine are shown to correspond with increasing treatment amounts of PD1-Fc-OX40L (panel K shows, left to right, untreated, 40 ug×1, 40 ug×2, 100 ug×1, and 100 ug×2). Panel L shows CT26 tumor growth kinetics for each treatment group.

FIG. 12, panel A shows the predicted tertiary structure of human PD-1-Fc-OX40L as determined by RaptorX. Panel B shows immunogenicity assessment of human PD-1-Fc-OX40 using iTope, an in silico modeling algorithm (ANTITOPE/ABZENA), cross referenced to a proprietary T cell epitope database.

FIG. 13 shows characterization of human PD-1-Fc-OX40L (also referred to as SL-279252). Panel A shows protein A elution peaks (OD₄₅₀) from SL-279252 purified from stable (in-house) and or transient transfection (Thermo) preparations. ELISA results from each elution peak are overlayed on the absorbance readings to indicate that the SL279252 protein is contained within the first elution peak from the column. Panel B shows Western blot analysis of SL-279252, performed by probing purified protein with human anti-PD-1 (left gel), anti-Fc (middle gel), and anti-OX40L (right gel) antibodies, under non-reducing and reducing conditions, and with or without the deglycosylase PNGase F. The predicted molecular weight of monomeric SL-279252 is 60.3 kDa. Panel C shows results from functional ELISAs using capturing with recombinant hOX40 and detection with Gt-hOX40L/Gt-HRP as compared to a recombinant human OX40L-Fc standard. Panel D shows results from functional ELISAs designed to test functional binding for each side of SL-279252 simultaneously. Specifically, recombinant human PD-L1 was absorbed to a plate and used to capture SL-279252. Captured protein was then detected using recombinant hOX40-his/HRP rabbit anti-his versus HVEM-his as a negative control for specificity.

FIG. 14 shows surface plasmon resonance (SPR) and half-life analysis of SL-279252. The ‘on-rate (Ka)’, ‘off-rate (Kd)’, and binding affinity (K_(D)) were determined for SL-279252, when binding to human PD-L1 (panel A), human PD-L2 (panel B), human OX40 (panel C), human FcγR1A (panel D), and FcRn (panel E), compared with the appropriate controls. Panel F summarizes the on-rate (Ka), off rate (Kd), and binding affinity (KD) for each condition tested. The binding of a modified SL-279252 construct containing a distinct leader peptide as well as mutations in the Fc region to increase binding to FcRn was also tested when binding to human PD-L1 (panel G), human PD-L2 (panel H), human OX40 (panel I), human FcγR1A (panel J), and FcRn (panel K), compared with the appropriate controls. Panel L summarizes the on-rate (Ka), off rate (Kd), and binding affinity (KD) for each condition tested. Panel M shows the in vivo serum half-life of SL-279252 in C57BL/6 mice. Panel N shows the in vivo intra-tumoral half-life of SL-279252 in immunocompromised (NSG) mice that were implanted with human PD-L1 positive tumor on flank (HeLa-PD-L1) and PD-L1 negative tumor on the opposite flank (HeLa). On the indicated days, the two tumors were excised and bi-sected. Half of the bisected tumor was disaggregated and tested for SL-279252 binding by flow cytometry using antibodies against human OX40L. Panel O shows frozen sections from the other half of the bisected tumors 6 hours, 2 days and 5 days after treatment with a single injection of SL-279252. The figure indicates persistence of SL-279252 at least 5 days following administration.

FIG. 15 shows binding of SL-279252 to cells in vitro. In panel A, parental Jurkat (cell population to the left) and Jurkat/hOX40 (cell population to the right) cells were assessed by flow cytometry using a hOX40-APC antibody. In panel B, parental CHO-K1 cells (cell population to the left) and CHO-K1/hPD-L1 (cell population to the right) were assessed by flow cytometry using a hPD-L1-APC antibody. In panel C, parental CHO-K1 cells (cell population to the left) and CHO-K1/hCD47 (cell population to the right) were assessed by flow cytometry using a hCD47-APC antibody. In panel D, increasing concentrations of SL-279252 were incubated with parental CHO-K1 cells (left panel) and CHO-K1/hPD-L1 (middle panel) and detected with anti-human OX40L-APC antibody. The right panel shows the titration curve for increasing concentrations of SL-279252. In panel E, increasing concentrations of SL-279252 were incubated with parental Jurkat cells (left panel) or Jurkat/hOX40 cells (middle panel) and detected with anti-human OX40L-APC antibody. The right panel shows the titration curve for increasing concentrations of SL-279252. In panel F, increasing concentrations of hCD172a-Fc-OX40L were incubated with parental CHO-K1 cells (left panel) or CHO-K1-CD47 cells (middle panel) and detected with an anti-human OX40L-APC antibody. The right panel shows the titration curve for increasing concentrations of hCD172a-Fc-OX40L. Panel G shows binding of increasing concentrations of hCD172a-Fc-OX40L to parental Jurkat cells (left panel) or Jurkat-hOX40 cells (middle panel). The right panel shows the titration curve for increasing concentrations of hCD172a-Fc-OX40L. In panel H, human PD-L1_(low) (PC3 cells; cell population to the left) and PD-L1_(high) (HCC827; cell population to the right) were identified by flow cytometry. In panel I, increasing concentrations of SL-279252 were incubated with PC3 cells. In panel J, increasing concentrations of SL-279252 were incubated with HCC827 cells for 2 hours. Cells were washed and analyzed by flow cytometry for SL-279252 binding (Fc-PE antibody).

FIG. 16 shows the ex vivo functional characterization of SL-279252. In panel A, OX40 expression was detected in human T cells isolated from PBMCs treated for 2 days with PMA/PHA/Ionomycin (Ion.). In panel B, binding of SL-279252 was assessed in activated CD4+ and CD8+ cells (Fc-PE secondary). Panel C provides a schematic representation of a T cell/tumor co-culture assay to detect T cell activation as well as a time-line for the experiment. In panel D, co-culture media was assessed by IL2 ELISA 6 days after initial T cell isolation. The line graphs, from left to right, represent +PC3 (−FP), +PC3 (+500 ng FP), +PC3 (+5 ug FP), +HCC827 (−FP), +HCC827 (+500 ng FP), and +HCC827 (+5 ug FP). In panel E, co-cultured T cells were analyzed by flow cytometry 5 days after initial isolation for proliferation of CD4+ and CD8+ cells (Ki67) and 7 days after isolation for cytokine expression in CD8+ cells. The line graphs, from left to right, represent +HCC827 (−FP), +HCC827 (+500 ng FP), and +HCC827 (+5 ug FP).

FIG. 17, panel A shows Western blot analysis of various chimeric proteins including hCD172a-Fc-OX40L, hPD1-Fc-TL1A, hBTLA-Fc-OX40L, hTMIGD2-Fc-OX40L, hTIM3-Fc-OX40L, mPD1-Fc-GITRL, mPD1-Fc-4-1BBL, mPD1-Fc-TL1A, mCD172a-Fc-CD40L. Each chimeric protein was probed with antibodies specific for each binding end and the central Fc domain. ELISA assays were performed to confirm binding of various chimeric proteins to human OX40. Panel B shows a schematic representation of the ELISA method used to detect binding of chimeric proteins to human OX40. Panel C shows results of human PD1-Fc-OX40L binding to parental Jurkat cells (left panel, left curve) or to Jurkat/OX40 cells (left panel, right curve). Two negative controls were used to demonstrate specificity: human PD1-Fc-TL1A (middle panel) and canine PD1-Fc-OX40L (right panel). Panel D shows the predicted tertiary structure of a human CD172a-Fc-OX40L as determined by RaptorX. Panel E shows an example production and purification of human PD1-Fc-OX40L (SL-279252) including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel F shows an example production and purification of human CD172a-Fc-OX40L including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel G shows an example production and purification of mouse CD172a-Fc-CD40L including the purification parameters (upper table) and the LabChip purified protein analysis (lower panel). Panel H shows an example production and purification of human TIGIT-Fc-OX40L including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel I shows the binding affinity of human CD172a-Fc-OX40L to immobilized recombinant CD47. Panel J shows the binding affinity of human CD172a-Fc-OX40L to immobilized recombinant human OX40. Panel K shows the binding affinity of human CD172a-Fc-OX40L to immobilized recombinant human FcγR1A. Panel L shows the binding affinity of human CD172a-Fc-OX40L to immobilized recombinant human FcRn. Panel M shows a summary of the on-rate (Ka), off-rate (Kd), and binding affinity (KD) for each condition tested. Panel N shows an example production and purification of canine PD1-Fc-OX40L including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel O shows an example production and purification of mouse PD1-Fc-OX40L including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel P shows an example production and purification of mouse PD1-Fc-GITRL including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel Q shows an example production and purification of mouse PD1-Fc-41BBL including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel R shows an example production and purification of mouse PD1-Fc-TL1A including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel S shows an example production and purification of mouse CD115-Fc-CD40L including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right). Panel T shows an example production and purification of human PD1-Fc-GITRL including the Coomassie-Gel (upper left), anti-IgG Western blot (upper right), eluted protein concentration (lower left) and elution profile from affinity chromatography (lower right).

DETAILED DESCRIPTION

The present invention is based, in part, on the discovery that chimeric proteins can be engineered from the extracellular, or effector, regions of immune-modulating transmembrane proteins in a manner that exploits the orientations of these proteins (e.g. type I versus type II) and therefore allows the delivery of immune stimulatory and/or immune inhibitory signals, including, for example, masking an immune inhibitory signal and replacing it with an immune stimulatory signal in the treatment of cancer.

Chimeric Proteins

In one aspect, the present invention relates to a chimeric protein comprising: (a) a first extracellular domain of a type I transmembrane protein at or near the N-terminus, (b) a second extracellular domain of a type II transmembrane protein at or near the C-terminus, and (c) a linker, wherein one of the first and second extracellular domains is an immune inhibitory signal and one of the first and second extracellular domains is an immune stimulatory signal.

In some embodiments, chimeric protein refers to a recombinant fusion protein, e.g. a single polypeptide having the extracellular domains described herein (and, optionally a linker). For example, in various embodiments, the chimeric protein is translated as a single unit in a cell. In some embodiments, chimeric protein refers to a recombinant protein of multiple polypeptides, e.g. multiple extracellular domains described herein, that are linked to yield a single unit, e.g. in vitro (e.g. with one or more synthetic linkers described herein).

In some embodiments, an extracellular domain refers to a portion of a transmembrane protein which is capable of interacting with the extracellular environment. In various embodiments, an extracellular domain refers to a portion of a transmembrane protein which is sufficient to bind to a ligand or receptor and effective transmit a signal to a cell. In various embodiments, an extracellular domain is the entire amino acid sequence of a transmembrane protein which is external of a cell or the cell membrane. In various embodiments, an extracellular domain is the that portion of an amino acid sequence of a transmembrane protein which is external of a cell or the cell membrane and is needed for signal transduction and/or ligand binding as may be assayed using methods know in the art (e.g. in vitro ligand binding and/or cellular activation assays).

In some embodiments, an immune inhibitory signal refers to a signal that diminishes or eliminates an immune response. For example, in the context of oncology, such signals may diminish or eliminate antitumor immunity. Under normal physiological conditions, inhibitory signal are useful in the maintenance of self-tolerance (e.g. prevention of autoimmunity) and also to protect tissues from damage when the immune system is responding to pathogenic infection. For instance, without limitation, immune inhibitory signal may be identified by detecting an increase in cellular proliferation, cytokine production, cell killing activity or phagocytic activity when such an inhibitory signal is blocked. Specific examples such inhibitory signals include blockade of PD-1 of PD-L1/L2 using antibody mediated blockade or through competitive inhibition of PD-L1/L2 using PD-1 containing fusion proteins. When such an inhibitory signal is blocked through inhibition of PD-L1/L2, it leads to enhance tumor killing activity by T cells because they are no longer being inhibited by PD-L1 or PD-L2. In another example, and inhibitory signal may be provided by CD47 to macrophages expressing CD172a. Binding of CD47 to CD172a typically inhibits the ability of a macrophage to phagocytose a target cell, which can be restored through blockade of CD47 with blocking antibodies or through competitive inhibition of CD47 using CD172a containing fusion proteins.

In some embodiments, an immune stimulatory signal refers to a signal that enhances an immune response. For example, in the context of oncology, such signals may enhance antitumor immunity. For instance, without limitation, immune stimulatory signal may be identified by directly stimulating proliferation, cytokine production, killing activity or phagocytic activity of leukocytes. Specific examples include direct stimulation of TNF superfamily receptors such as OX40, 4-1BB or TNFRSF25 using either receptor agonist antibodies or using fusion proteins encoding the ligands for such receptors (OX40L, 4-1BBL, TL1A, respectively). Stimulation from any one of these receptors may directly stimulate the proliferation and cytokine production of individual T cell subsets. Another example includes direct stimulation of an immune inhibitory cell with through a receptor that inhibits the activity of such an immune suppressor cell. This would include, for example, stimulation of CD4+FoxP3+ regulatory T cells with a GITR agonist antibody or GITRL containing fusion protein, which would reduce the ability of those regulatory T cells to suppress the proliferation of conventional CD4+ or CD8+ T cells. In another example, this would include stimulation of CD40 on the surface of an antigen presenting cell using a CD40 agonist antibody or a fusion protein containing CD40L, causing activation of antigen presenting cells including enhanced ability of those cells to present antigen in the context of appropriate native costimulatory molecules, including those in the B7 or TNF superfamily.

Membrane proteins typically consist of an extracellular domain, one or a series of trans-membrane domains, and an intracellular domain. Without wishing to be bound by theory, the extracellular domain of a membrane protein is responsible for interacting with a soluble or membrane bound receptor or ligand. Without wishing to be bound by theory, the trans-membrane domain(s) are responsible for localizing a protein to the plasma membrane. Without wishing to be bound by theory, the intracellular domain of a membrane protein is responsible for coordinating interactions with cellular signaling molecules to coordinate intracellular responses with the extracellular environment (or visa-versa). There are two types of single-pass membrane proteins, those with an extracellular amino terminus and intracellular carboxy terminus (type I) and those with an extracellular carboxy terminus and intracellular amino terminus (type II). Both type I and type II membrane proteins can be either receptors or ligands. For type I membrane proteins, the amino terminus of the protein faces outside the cell, and therefore contains the functional domains that are responsible for interacting with other binding partners (either ligands or receptors) in the extracellular environment (FIG. 1, left image). For type II membrane proteins, the carboxy terminus of the protein faces outside the cell, and therefore contains the functional domains that are responsible for interacting with other binding partners (either ligands or receptors) in the extracellular environment (FIG. 1, right image). Thus, these two types of proteins have opposite orientations to each other.

Because the outward facing domains of type I and type II membrane proteins are opposite (FIG. 1), it is possible to link the extracellular domains of a type I and type II membrane protein such that the ‘outward facing’ domains of the molecules are also in opposing orientation to each other (FIG. 3). The resulting construct would therefore consist of the extracellular domain of a type I membrane protein on the ‘left’ side of the molecule, connected to the extracellular domain of a type II membrane protein on the ‘right’ side of the molecule using a linker sequence. This construct could be produced by cloning of these three fragments (the extracellular domain of a type I protein, followed by a linker sequence, followed by the extracellular domain of a type II protein) into a vector (plasmid, viral or other) wherein the amino terminus of the complete sequence corresponded to the ‘left’ side of the molecule containing the type I protein and the carboxy terminus of the complete sequence corresponded to the ‘right’ side of the molecule containing the type II protein. Accordingly, in various embodiments, the present chimeric proteins are engineered as such.

In some embodiments, the extracellular domain may be used to produce a soluble protein to competitively inhibit signaling by that receptor's ligand. In some embodiments, the extracellular domain may be used to provide artificial signaling.

In some embodiments, the extracellular domain of a type I transmembrane protein is an immune inhibitory signal. In some embodiments, the extracellular domain of a type II transmembrane protein is an immune stimulatory signal.

In some embodiments, the present chimeric proteins comprise an extracellular domain of a type I transmembrane protein, or a functional fragment thereof. In some embodiments, the present chimeric proteins comprise an extracellular domain of a type II transmembrane protein, or a functional fragment thereof. In some embodiments, the present chimeric proteins comprise an extracellular domain of a type I transmembrane protein, or a functional fragment thereof, and an extracellular domain of a type II transmembrane protein, or a functional fragment thereof.

In various embodiments, the present chimeric proteins comprise an extracellular domain of a human type I transmembrane protein as recited in TABLE 1, or a functional fragment thereof. In various embodiments, the present chimeric proteins comprise an extracellular domain of a human type II transmembrane protein as recited in TABLE 2, or a functional fragment thereof. In some embodiments, the present chimeric proteins comprise an extracellular domain of a type I transmembrane protein as recited in TABLE 1, or a functional fragment thereof, and an extracellular domain of a type II transmembrane protein as recited in TABLE 2, or a functional fragment thereof. TABLEs 1 and 2 are provided elsewhere herein.

In various embodiments, the present chimeric proteins may be engineered to target one or more molecules that reside on human leukocytes including, without limitation, the extracellular domains (where applicable) of SLAMF4, IL-2 R α, 4-1BB/TNFRSF9, IL-2 R β, ALCAM, B7-1, IL-4 R, B7-H3, BLAME/SLAMFS, CEACAM1, IL-6 R, IL-7 Rα, IL-10R α, IL-I 0 R β, IL-12 R β1, IL-12 R β 2, CD2, IL-13 R α 1, IL-13, CD3, CD4, ILT2/CDS5j, ILT3/CDS5k, ILT4/CDS5d, ILT5/CDS5a, Integrin α 4/CD49d, CDS, Integrin α E/CD103, CD6, Integrin α M/CD 11 b, CDS, Integrin α X/CD11c, Integrin β 2/CDIS, KIR/CD15S, CD27/TNFRSF7, KIR2DL1, CD2S, KIR2DL3, CD30/TNFRSFS, KIR2DL4/CD15Sd, CD31/PECAM-1, KIR2DS4, CD40 Ligand/TNFSF5, LAG-3, CD43, LAIR1, CD45, LAIR2, CDS3, Leukotriene B4-R1, CDS4/SLAMF5, NCAM-L1, CD94, NKG2A, CD97, NKG2C, CD229/SLAMF3, NKG2D, CD2F-10/SLAMF9, NT-4, CD69, NTB-A/SLAMF6, Common γ Chain/IL-2 R γ, Osteopontin, CRACC/SLAMF7, PD-1, CRTAM, PSGL-1, CTLA-4, RANK/TNFRSF11A, CX3CR1, CX3CL1, L-Selectin, SIRP β 1, SLAM, TCCR/WSX-1, DNAM-1, Thymopoietin, EMMPRIN/CD147, TIM-1, EphB6, TIM-2, Fas/TNFRSF6, TIM-3, Fas Ligand/TNFSF6, TIM-4, Fcγ RIII/CD16, TIM-6, TNFR1/TNFRSF1A, Granulysin, TNF RIII/TNFRSF1B, TRAIL RI/TNFRSFIOA, ICAM-1/CD54, TRAIL R2/TNFRSF10B, ICAM-2/CD102, TRAILR3/TNFRSF10C, IFN-γR1, TRAILR4/TNFRSF10D, IFN-γ R2, TSLP, IL-1 R1 and TSLP R.

The activation of regulatory T cells is critically influenced by costimulatory and coinhibitory signals. Two major families of costimulatory molecules include the B7 and the tumor necrosis factor (TNF) families. These molecules bind to receptors on T cells belonging to the CD28 or TNF receptor families, respectively. Many well-defined coinhibitors and their receptors belong to the B7 and CD28 families.

In various embodiments, the present chimeric proteins may be engineered to target one or more molecules involved in immune inhibition, including for example: CTLA-4, PD-L1, PD-L2, PD-1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA/VSIG8, KIR, 2B4, TIGIT, CD160 (also referred to as BY55), CHK 1 and CHK2 kinases, A2aR, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), and various B-7 family ligands (including, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7).

In various embodiments, the chimeric protein of the present invention comprises an extracellular domain of an immune inhibitory agent, including without limitation, one or more of TIM-3, BTLA, PD-1, CTLA-4, CD244, CD160, TIGIT, SIRPα/CD172a, 2B4, VISTA, VSIG8, LAG3, CD200 and TMIGD2.

In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of a type I membrane protein which has immune inhibitory properties. In various embodiments, the chimeric protein is engineered to disrupt, block, reduce, and/or inhibit the transmission of an immune inhibitory signal, by way of non-limiting example, the binding of PD-1 with PD-L1 or PD-L2 and/or the binding of CD172a with CD47 and/or the binding of TIM-3 with galectin-9 and/or phosphatidyserine.

In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of an immune stimulatory signal is one or more of OX-40 ligand (OX-40L), LIGHT (CD258), GITR ligand (GITRL), CD70, CD30 ligand, CD40 ligand (CD40L), CD137 ligand, TRAIL, and TL1A.

In various embodiments, the chimeric protein simulates binding of an inhibitory signal ligand to its cognate receptor (e.g. PD-1 to PD-L1 or PD-L2; e.g. CD172a to CD47; e.g. CD115 to CSF1; e.g. TIM-3 to galectin-9 or phosphatidylserine) but inhibits the inhibitory signal transmission to an immune cell (e.g. a T cell, macrophage or other leukocyte).

In various embodiments, the chimeric protein comprises an immune inhibitory receptor extracellular domain and an immune stimulatory ligand extracellular domain which can, without limitation, deliver an immune stimulation to a T cell while masking a tumor cell's immune inhibitory signals. In various embodiments, the chimeric protein delivers a signal that has the net result of T cell activation.

In some embodiments, the chimeric protein comprises an immune inhibitory signal which is an ECD of a receptor of an immune inhibitory signal and this acts on a tumor cell that bears a cognate ligand of the immune inhibitory signal. In some embodiments, the chimeric protein comprises an immune stimulatory signal which is an ECD of a ligand of an immune stimulatory signal and this acts on a T cell that bears a cognate receptor of the immune stimulatory signal. In some embodiments, the chimeric protein comprises both (i) an immune inhibitory signal which is a receptor of an immune inhibitory signal and this acts on a tumor cell that bears a cognate ligand of the immune inhibitory signal and (ii) an immune stimulatory signal which is a ligand of an immune stimulatory signal and this acts on a T cell that bears a cognate receptor of the immune stimulatory signal.

In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of one or more of the immune-modulating agents described in Mahoney, Nature Reviews Drug Discovery 2015:14; 561-585, the entire contents of which are hereby incorporated by reference. For example, with reference to present FIG. 2, the chimeric protein bears an immune inhibitory signal (denoted by “−”) which is a receptor of the pair (i.e. right side of the figure) and the tumor cell bears a ligand selected from the left side of the figure. By way of further example, with reference to present FIG. 2, the chimeric protein bears an immune stimulatory signal (denoted by “+”) which is a ligand of the pair (i.e. left side of the figure) and the tumor cell bears a receptor selected from the right side of the figure.

In some embodiments, the chimeric protein of the present invention comprises an extracellular domain of a type II membrane protein which has immune stimulatory properties. In various embodiments, the chimeric protein is engineered to enhance, increase, and/or stimulate the transmission of an immune stimulatory signal, by way of non-limiting example, the binding of GITR with one or more of GITR ligand and/or the binding of OX40 with OX40L and/or the binding of CD40 with CD40 ligand.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent PD-1 and is paired with an immune stimulatory agent as follows: PD-1/4-1BBL; PD-1/OX-40L; PD-1/LIGHT; PD-1/GITRL; PD-1/CD70; PD-1/CD30L; PD-1/CD40L; and PD-1/TL1A.

In an embodiment, the chimeric protein comprises the extracellular domain of the immune inhibitory agent PD-1 and is paired with the immune stimulatory agent OX-40L. In an embodiment, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 22. In various embodiments, the chimeric protein binds to human PD-L1 or PD-L2 with a K_(D) of about 1 nM to about 5 nM, for example, about 1 nM, about 1.5 nM, about 2 nM, about 2.5 nM, about 3 nM, about 3.5 nM, about 4 nM, about 4.5 nM, or about 5 nM. In various embodiments, the chimeric protein binds to human PD-L1 with a K_(D) of about 5 nM to about 15 nM, for example, about 5 nM, about 5.5 nM, about 6 nM, about 6.5 nM, about 7 nM, about 7.5 nM, about 8 nM, about 8.5 nM, about 9 nM, about 9.5 nM, about 10 nM, about 10.5 nM, about 11 nM, about 11.5 nM, about 12 nM, about 12.5 nM, about 13 nM, about 13.5 nM, about 14 nM, about 14.5 nM, or about 15 nM.

In various embodiments, the chimeric protein exhibits enhanced stability and protein half-life. In some embodiments, the chimeric protein binds to FcRn with high affinity. In various embodiments, the chimeric protein may bind to FcRn with a K_(D) of about 70 nM to about 80 nM. For example, the chimeric protein may bind to FcRn with a K_(D) of about 70 nM, about 71 nM, about 72 nM, about 73 nM, about 74 nM, about 75 nM, about 76 nM, about 77 nM, about 78 nM, about 79 nM, or about 80 nM. In some embodiments, the chimeric protein does not substantially bind to other Fc receptors (i.e. other than FcRn) with effector function.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent PD-L1 or PD-L2 and is paired with an immune stimulatory receptor as follows: PD-L1/4-1BB; PD-L1/OX-40; PD-L1/HVEM; PD-L1/GITR; PD-L1/CD27; PD-L1/CD28; PD-L1/CD30; PD-L1/CD40 and PD-L1/CD137.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent PD-L2 and is paired with an immune stimulatory receptor as follows: PD-L2/4-1BB; PD-L2/OX-40; PD-L2/HVEM; PD-L2/GITR; PD-L2/CD27; PD-L2/CD28; PD-L2/CD30; PD-L2/CD40 and PD-L2/CD137.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent TIM-3 and is paired with an immune stimulatory agent as follows: TIM-3/OX-40L; TIM-3/LIGHT; TIM-3/GITRL; TIM-3/CD70; TIM-3/CD30L; TIM-3/CD40L; TIM-3/CD137L; TIM-3/TL1A; and TIM-3/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent BTLA and is paired with an immune stimulatory agent as follows: BTLA/OX-40L; BTLA/LIGHT; BTLA/GITRL; BTLA/CD70; BTLA/CD30L; BTLA/CD40L; BTLA/CD137L; BTLA/TL1A; and BTLA/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent CD172a/SIRPα and is paired with an immune stimulatory agent as follows: CD172a/OX-40L; CD172a/LIGHT; CD172a/CD70; CD172a/CD30L; CD172a/CD40L; CD172a/CD137L; CD172a/TL1A; and CD172a/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent CD115 and is paired with an immune stimulatory agent as follows: CD115/OX-40L; CD115/LIGHT; CD115/CD70; CD115/CD30L; CD115/CD40L; CD115/CD137L; CD115/TL1A; and CD115/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent TIGIT and is paired with an immune stimulatory agent as follows: TIGIT/OX-40L; TIGIT/LIGHT; TIGIT/GITRL; TIGIT/CD70; TIGIT/CD30L; TIGIT/CD40L; TIGIT/CD137L; TIGIT/TL1A; and TIGIT/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent TMIGD2 and is paired with an immune stimulatory agent as follows: TMIGD2/OX-40L; TMIGD2/LIGHT; TMIGD2/GITRL; TMIGD2/CD70; TMIGD2/CD30L; TMIGD2/CD40L; TMIGD2/CD137L; TMIGD2/TL1A; and TMIGD2/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent LAG3 and is paired with an immune stimulatory agent as follows: LAG3/OX-40L; LAG3/LIGHT; LAG3/GITRL; LAG3/CD70; LAG3/CD30L; LAG3/CD40L; LAG3/CD137L; LAG3/TL1A; and LAG3/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent VSIG8 and is paired with an immune stimulatory agent as follows: VSIG8/OX-40L; VSIG8/LIGHT; VSIG8/GITRL; VSIG8/CD70; VSIG8/CD30L; VSIG8/CD40L; VSIG8/CD137L; VSIG8/TL1A; and VSIG8/OX40L.

In some embodiments, the chimeric protein comprises the extracellular domain of the immune inhibitory agent CD200 and is paired with an immune stimulatory agent as follows: CD200/OX-40L; CD200/LIGHT; CD200/GITRL; CD200/CD70; CD200/CD30L; CD200/CD40L; CD200/CD137L; CD200/TL1A; and CD200/OX40L.

In various embodiments, the present chimeric proteins may comprises variants of the extracellular domains described herein, for instance, a sequence having at least about 60%, or at least about 61%, or at least about 62%, or at least about 63%, or at least about 64%, or at least about 65%, or at least about 66%, or at least about 67%, or at least about 68%, or at least about 69%, or at least about 70%, or at least about 71%, or at least about 72%, or at least about 73%, or at least about 74%, or at least about 75%, or at least about 76%, or at least about 77%, or at least about 78%, or at least about 79%, or at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%) sequence identity with the known amino acid or nucleic acid sequence of the extracellular domains, e.g. human extracellular domains, e.g. one or more of SEQ IDs NOs: 1-15 as a whole or relative to indicated domains therein. Included herein are various illustrative sequences, as SEQ IDs NOs: 1-15, which show extracellular domains as underlined or in bold and a linker in normal text. In various embodiments, the linker can be swapped for another described herein.

In an illustrative embodiment, the chimeric protein of the present invention comprises an extracellular domain of PD-1 and the extracellular domain of OX40L using the hinge-CH2-CH3 domain from a human IgG4 antibody sequence. In this embodiment, the extracellular domain of PD-1 is underlined, followed by the hinge-CH2-CH3 domain of human IgG4 and short linker (normal text), followed by the extracellular domain of OX40L (bold text):

(SEQ ID NO: 1) ATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCT ACAACTGGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAG GCCCTGGAACCCCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGAC CGAAGGGGACAACGCCACCTTCACCTGCAGCTTCTCCAACACATC GGAGAGCTTCGTGCTAAACTGGTACCGCATGAGCCCCAGCAACCA GACGGACAAGCTGGCCGCCTTCCCCGAGGACCGCAGCCAGCCCG GCCAGGACTGCCGCTTCCGTGTCACACAACTGCCCAACGGGCGT GACTTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGACAGCGG CACCTACCTCTGTGGGGCCATCTCCCTGGCCCCCAAGGCGCAGAT CAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAGAGAAGGG CAGAAGTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGCC GGCCAGTTCCAATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCC GCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCA AAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGAC CTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTT CAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAA GCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGT GCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAA GTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGA CCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTAC ACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCC CTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTG GAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCAC CCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCG GCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCA GCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGA AGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACC AGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAAT TTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAA AGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATC AACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCC CAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCC CCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGT GGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTGACCAC TGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACT GATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTTTGA.

This sequence encodes a protein with an amino acid sequence:

(SEQ ID NO: 2) M Q I P Q A P W P V V W A V L Q L G W R P G W F L D S P D R P W N P P T F S P A L L V V T E G D N A T F T C S F S N T S E S F V L N W Y R M S P S N Q T D K L A A F P E D R S Q P G Q D C R F R V T Q L P N G R D F H M S V V R A R R N D S G T Y L C G A I S L A P K A Q I K E S L R A E L R V T E R R A E V P T A H P S P S P R P A G Q F Q S K Y G P P C P S C P A P E F L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S Q E D P E V Q F N W Y V D G V E V H N A K T K P R E E Q F N S T Y R V V S V L T V L H Q D W L S G K E Y K C K V S S K G L P S S I E K T I S N A T G Q P R E P Q V Y T L P P S Q E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S R L T V D K S S W Q E G N V F S C S V M H E A L H N H Y T Q K S L S L S L G K I E G R M D Q V S H R Y P R I Q S I K V Q F T E Y K K E K G F I L T S Q K E D E I M K V Q N N S V I I N C D G F Y L I S L K G Y F S Q E V N I S L H Y Q K D E E P L F Q L K K V R S V N S L M V A S L T Y K D K V Y L N V T T D N T S L D D F H V N G G E L I L I H Q N P G E F C V L Stop

Further, this amino acid sequence, as well as the amino acid sequences of any of the extracellular domains described herein (whether or not explicitly listed) could also be achieved with codon-optimized nucleic acid sequences, such as the following sequence which is optimized for expression by Chinese Hamster (CHO) cells:

(SEQ ID NO: 3) ATGCAGATTCCTCAGGCCCCTTGGCCTGTCGTGTGGGCTGTGCTG CAGCTGGGATGGCGGCCTGGCTGGTTTCTGGACAGCCCCGACAG ACCCTGGAACCCCCCTACATTTTCCCCTGCCCTGCTGGTCGTGAC CGAGGGCGACAATGCCACCTTCACCTGTAGCTTCAGCAACACCAG CGAGAGCTTCGTGCTGAACTGGTACAGAATGAGCCCCAGCAACCA GACCGACAAGCTGGCCGCCTTCCCCGAGGATAGATCTCAGCCCG GCCAGGACTGCCGGTTCAGAGTGACCCAGCTGCCCAACGGCCGG GACTTCCACATGTCTGTCGTGCGGGCCAGACGGAACGACAGCGG CACATATCTGTGCGGCGCCATCAGCCTGGCCCCCAAGGCCCAGAT CAAAGAGAGCCTGAGAGCCGAGCTGAGAGTGACCGAGAGAAGGG CCGAAGTGCCTACCGCCCACCCTAGCCCATCTCCAAGACCTGCCG GCCAGTTCCAGTCTAAGTACGGCCCTCCTTGCCCCAGCTGTCCCG CCCCTGAATTTCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAA AGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCT GCGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTC AATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAG CCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCCGTG CTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAG TGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAGAAAAC CATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACA CACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCC TGACCTGTCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGG AATGGGAGAGCAACGGCCAGCCTGAGAACAACTACAAGACCACCC CCCCAGTGCTGGACAGCGACGGCTCATTTTTCCTGTACTCCAGAC TGACCGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGC TGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAG TCCCTGTCTCTGAGCCTGGGCAAGATCGAGGGCCGGATGGATAG AGCCCAGGGCGAAGCCTGCGTGCAGTTCCAGGCTCTGAAGGGC CAGGAATTCGCCCCCAGCCACCAGCAGGTGTACGCCCCTCTGAG AGCTGACGGCGACAAGCCTAGAGCCCACCTGACAGTCGTGCGG CAGACCCCTACCCAGCACTTCAAGAATCAGTTCCCAGCCCTGCA CTGGGAGCACGAGCTGGGCCTGGCCTTCACCAAGAACAGAATGA ACTACACCAACAAGTTTCTGCTGATCCCCGAGAGCGGCGACTAC TTCATCTACAGCCAAGTGACCTTCCGGGGCATGACCAGCGAGTG CAGCGAGATCAGACAGGCCGGCAGACCTAACAAGCCCGACAGC ATCACCGTCGTGATCACCAAAGTGACCGACAGCTACCCCGAGCC CACACAGCTGCTGATGGGCACCAAGAGCGTGTGCGAAGTGGGC AGCAACTGGTTCCAGCCCATCTACCTGGGCGCCATGTTCAGTCTG CAAGAGGGCGATAAGCTGATGGTCAACGTGTCCGACATCTCCCT GGTGGATTACACCAAAGAGGACAAGACCTTCTTCGGCGCCTTTCT GCTCTGA

Another embodiment of the present chimeric protein comprises the extracellular domain of PD-1 and the extracellular domain of costimulatory ligand, such as TL1A, 4-1BBL, ICOSL, GITRL, CD27 or CD40L. An example sequence encoding the extracellular domain of PD-1 (underlined)—Fc (normal text)—the extracellular domain of TL1A (bold text) is:

(SEQ ID NO: 4) ATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCT ACAACTGGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAG GCCCTGGAACCCCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGAC CGAAGGGGACAACGCCACCTTCACCTGCAGCTTCTCCAACACATC GGAGAGCTTCGTGCTAAACTGGTACCGCATGAGCCCCAGCAACCA GACGGACAAGCTGGCCGCCTTCCCCGAGGACCGCAGCCAGCCCG GCCAGGACTGCCGCTTCCGTGTCACACAACTGCCCAACGGGCGT GACTTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGACAGCGG CACCTACCTCTGTGGGGCCATCTCCCTGGCCCCCAAGGCGCAGAT CAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAGAGAAGGG CAGAAGTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGCC GGCCAGTTCCAATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCC GCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCA AAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGAC CTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTT CAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAA GCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGT GCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAA GTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGA CCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTAC ACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCC CTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTG GAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCAC CCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCG GCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCA GCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGA AGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACC GGGCCCAGGGAGAGGCCTGTGTGCAGTTCCAGGCTCTAAAAGG ACAGGAGTTTGCACCTTCACATCAGCAAGTTTATGCACCTCTTAG AGCAGACGGAGATAAGCCAAGGGCACACCTGACAGTTGTGAGA CAAACTCCCACACAGCACTTTAAAAATCAGTTCCCAGCTCTGCAC TGGGAACATGAACTAGGCCTGGCCTTCACCAAGAACCGAATGAA CTATACCAACAAATTCCTGCTGATCCCAGAGTCGGGAGACTACTT CATTTACTCCCAGGTCACATTCCGTGGGATGACCTCTGAGTGCAG TGAAATCAGACAAGCAGGCCGACCAAACAAGCCAGACTCCATCA CTGTGGTCATCACCAAGGTAACAGACAGCTACCCTGAGCCAACC CAGCTCCTCATGGGGACCAAGTCTGTATGCGAAGTAGGTAGCAA CTGGTTCCAGCCCATCTACCTCGGAGCCATGTTCTCCTTGCAAGA AGGGGACAAGCTAATGGTGAACGTCAGTGACATCTCTTTGGTGG ATTACACAAAAGAAGATAAAACCTTCTTTGGAGCCTTCTTACTAT AG

This nucleotide sequence of SEQ ID NO: 4 may be codon optimized, to encode a protein with an amino acid sequence:

(SEQ ID NO: 5) M Q I P Q A P W P V V W A V L Q L G W R P G W F L D S P D R P W N P P T F S P A L L V V T E G D N A T F T C S F S N T S E S F V L N W Y R M S P S N Q T D K L A A F P E D R S Q P G Q D C R F R V T Q L P N G R D F H M S V V R A R R N D S G T Y L C G A I S L A P K A Q I K E S L R A E L R V T E R R A E V P T A H P S P S P R P A G Q F Q S K Y G P P C P S C P A P E F L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S Q E D P E V Q F N W Y V D G V E V H N A K T K P R E E Q F N S T Y R V V S V L T V L H Q D W L S G K E Y K C K V S S K G L P S S I E K T I S N A T G Q P R E P Q V Y T L P P S Q E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S R L T V D K S S W Q E G N V F S C S V M H E A L H N H Y T Q K S L S L S L G K I E G R M D R A Q G E A C V Q F Q A L K G Q E F A P S H Q Q V Y A P L R A D G D K P R A H L T V V R Q T P T Q H F K N Q F P A L H W E H E L G L A F T K N R M N Y T N K F L L I P E S G D Y F I Y S Q V T F R G M T S E C S E I R Q A G R P N K P D S I T V V I T K V T D S Y P E P T Q L L M G T K S V C E V G S N W F Q P I Y L G A M F S L Q E G D K L M V N V S D I S L V D Y T K E D K T F F G A F L L Stop

There are many type I membrane proteins expressed by tumor cells that could be masked by a fusion protein encoding the extracellular domain of a cognate receptor. Additional examples would include a fusion protein encoding the extracellular domain of BTLA, linked through an Fc to OX40L. Such a construct could be encoded by the nucleic acid sequence:

(SEQ ID NO: 6) ATGAAGACATTGCCTGCCATGCTTGGAACTGGGAAATTATTTTGGG TCTTCTTCTTAATCCCATATCTGGACATCTGGAACATCCATGGGAA AGAATCATGTGATGTACAGCTTTATATAAAGAGACAATCTGAACACT CCATCTTAGCAGGAGATCCCTTTGAACTAGAATGCCCTGTGAAATA CTGTGCTAACAGGCCTCATGTGACTTGGTGCAAGCTCAATGGAAC AACATGTGTAAAACTTGAAGATAGACAAACAAGTTGGAAGGAAGAG AAGAACATTTCATTTTTCATTCTACATTTTGAACCAGTGCTTCCTAAT GACAATGGGTCATACCGCTGTTCTGCAAATTTTCAGTCTAATCTCA TTGAAAGCCACTCAACAACTCTTTATGTGACAGATGTAAAAAGTGC CTCAGAACGACCCTCCAAGGACGAAATGGCAAGCTCTAAGTACGG CCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGGCGGACC CTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGAT CAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCC AGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTG GAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAAC AGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGAT TGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGG CCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCACCGGCCA GCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCCAGGAAG AGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGAAGGGCT TCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGC CAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACG GCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCT GGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCC CTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGC AAAATAGAGGGACGAATGGACCAGGTATCACATCGGTATCCTCGA ATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAGGAGAAA GGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTG CAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATC TCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAGCCTTCAT TACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGAAGGTCAG GTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAA AGTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTT CCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAAATCCTGG TGAATTCTGTGTCCTTTGA

This nucleotide sequence encodes a protein with an amino acid sequence:

(SEQ ID NO: 7) M K T L P A M L G T G K L F W V F F L I P Y L D I W N I H G K E S C D V Q L Y I K R Q S E H S I L A G D P F E L E C P V K Y C A N R P H V T W C K L N G T T C V K L E D R Q T S W K E E K N I S F F I L H F E P V L P N D N G S Y R C S A N F Q S N L I E S H S T T L Y V T D V K S A S E R P S K D E M A S S K Y G P P C P S C P A P E F L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S Q E D P E V Q F N W Y V D G V E V H N A K T K P R E E Q F N S T Y R V V S V L T V L H Q D W L S G K E Y K C K V S S K G L P S S I E K T I S N A T G Q P R E P Q V Y T L P P S Q E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S R L T V D K S S W Q E G N V F S C S V M H E A L H N H Y T Q K S L S L S L G K I E G R M D Q V S H R Y P R I Q S I K V Q F T E Y K K E K G F I L T S Q K E D E I M K V Q N N S V I I N C D G F Y L I S L K G Y F S Q E V N I S L H Y Q K D E E P L F Q L K K V R S V N S L M V A S L T Y K D K V Y L N V T T D N T S L D D F H V N G G E L I L I H Q N P G E F C V L Stop

Another example would include a fusion protein incorporating the extracellular domain of TIGIT, linked via an Fc linker to OX40L:

(SEQ ID NO: 8) ATGCGCTGGTGTCTCCTCCTGATCTGGGCCCAGGGGCTGAGGCA GGCTCCCCTCGCCTCAGGAATGATGACAGGCACAATAGAAACAAC GGGGAACATTTCTGCAGAGAAAGGTGGCTCTATCATCTTACAATGT CACCTCTCCTCCACCACGGCACAAGTGACCCAGGTCAACTGGGAG CAGCAGGACCAGCTTCTGGCCATTTGTAATGCTGACTTGGGGTGG CACATCTCCCCATCCTTCAAGGATCGAGTGGCCCCAGGTCCCGGC CTGGGCCTCACCCTCCAGTCGCTGACCGTGAACGATACAGGGGA GTACTTCTGCATCTATCACACCTACCCTGATGGGACGTACACTGGG AGAATCTTCCTGGAGGTCCTAGAAAGCTCAGTGGCTGAGCACGGT GCCAGGTTCCAGATTCCATCTAAGTACGGCCCTCCCTGCCCTAGC TGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTC CCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGA AGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGGT GCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCAA GACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGGT GTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGA GTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCG AAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAG GTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAG GTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATC GCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAA GACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTGTA CTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAACG TGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTACA CCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACGAA TGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAG TACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCACTT CCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAGTC ATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTAC TTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAG GAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCCTTG ATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAATGTG ACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGG AGAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTT TGA.

This sequence could be codon optimized to encode a protein with an amino acid sequence:

(SEQ ID NO: 9) M R W C L L L I W A Q G L R Q A P L A S G M M T G T I E T T G N I S A E K G G S I I L Q C H L S S T T A Q V T Q V N W E Q Q D Q L L A I C N A D L G W H I S P S F K D R V A P G P G L G L T L Q S L T V N D T G E Y F C I Y H T Y P D G T Y T G R I F L E V L E S S V A E H G A R F Q I P S K Y G P P C P S C P A P E F L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S Q E D P E V Q F N W Y V D G V E V H N A K T K P R E E Q F N S T Y R V V S V L T V L H Q D W L S G K E Y K C K V S S K G L P S S I E K T I S N A T G Q P R E P Q V Y T L P P S Q E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S R L T V D K S S W Q E G N V F S C S V M H E A L H N H Y T Q K S L S L S L G K I E G R M D Q V S H R Y P R I Q S I K V Q F T E Y K K E K G F I L T S Q K E D E I M K V Q N N S V I I N C D G F Y L I S L K G Y F S Q E V N I S L H Y Q K D E E P L F Q L K K V R S V N S L M V A S L T Y K D K V Y L N V T T D N T S L D D F H V N G G E L I L I H Q N P G E F C V L Stop.

Another example would include a fusion protein incorporating the extracellular domain of TIM3, linked through an Fc region to human OX40L:

(SEQ ID NO: 10) ATGTTTTCACATCTTCCCTTTGACTGTGTCCTGCTGCTGCTGCTGC TACTACTTACAAGGTCCTCAGAAGTGGAATACAGAGCGGAGGTCG GTCAGAATGCCTATCTGCCCTGCTTCTACACCCCAGCCGCCCCAG GGAACCTCGTGCCCGTCTGCTGGGGCAAAGGAGCCTGTCCTGTG TTTGAATGTGGCAACGTGGTGCTCAGGACTGATGAAAGGGATGTG AATTATTGGACATCCAGATACTGGCTAAATGGGGATTTCCGCAAAG GAGATGTGTCCCTGACCATAGAGAATGTGACTCTAGCAGACAGTG GGATCTACTGCTGCCGGATCCAAATCCCAGGCATAATGAATGATG AAAAATTTAACCTGAAGTTGGTCATCAAACCAGCCAAGGTCACCCC TGCACCGACTCGGCAGAGAGACTTCACTGCAGCCTTTCCAAGGAT GCTTACCACCAGGGGACATGGCCCAGCAGAGACACAGACACTGG GGAGCCTCCCTGATATAAATCTAACACAAATATCCACATTGGCCAA TGAGTTACGGGACTCTAGATTGGCCAATGACTTACGGGACTCTGG AGCAACCATCAGAATAGGCTCTAAGTACGGCCCTCCCTGCCCTAG CTGTCCCGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTT CCCCCCAAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCG AAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAAGATCCCGAGG TGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAACGCCA AGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTG GTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAA GAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCAT CGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCC AGGTGTACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACC AGGTGTCCCTGACATGCCTCGTGAAGGGCTTCTACCCCTCCGATA TCGCCGTGGAATGGGAGAGCAACGGCCAGCCAGAGAACAACTAC AAGACCACCCCCCCAGTGCTGGACAGCGACGGCTCATTCTTCCTG TACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAAGGCAA CGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTA CACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATAGAGGGACG AATGGACCAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAA AGTACAATTTACCGAATATAAGAAGGAGAAAGGTTTCATCCTCAC TTCCCAAAAGGAGGATGAAATCATGAAGGTGCAGAACAACTCAG TCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCT ACTTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATG AGGAGCCCCTCTTCCAACTGAAGAAGGTCAGGTCTGTCAACTCC TTGATGGTGGCCTCTCTGACTTACAAAGACAAAGTCTACTTGAAT GTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGC GGAGAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTC CTTTGA.

Such a sequence could be codon optimized to encode a protein with an amino acid sequence:

(SEQ ID NO: 11) M F S H L P F D C V L L L L L L L L T R S S E V E Y R A E V G Q N A Y L P C F Y T P A A P G N L V P V C W G K G A C P V F E C G N V V L R T D E R D V N Y W T S R Y W L N G D F R K G D V S L T I E N V T L A D S G I Y C C R I Q I P G I M N D E K F N L K L V I K P A K V T P A P T R Q R D F T A A F P R M L T T R G H G P A E T Q T L G S L P D I N L T Q I S T L A N E L R D S R L A N D L R D S G A T I R I G S K Y G P P C P S C P A P E F L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S Q E D P E V Q F N W Y V D G V E V H N A K T K P R E E Q F N S T Y R V V S V L T V L H Q D W L S G K E Y K C K V S S K G L P S S I E K T I S N A T G Q P R E P Q V Y T L P P S Q E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S R L T V D K S S W Q E G N V F S C S V M H E A L H N H Y T Q K S L S L S L G K I E G R M D Q V S H R Y P R I Q S I K V Q F T E Y K K E K G F I L T S Q K E D E I M K V Q N N S V I I N C D G F Y L I S L K G Y F S Q E V N I S L H Y Q K D E E P L F Q L K K V R S V N S L M V A S L T Y K D K V Y L N V T T D N T S L D D F H V N G G E L I L I H Q N P G E F C V L Stop.

Another example could include the extracellular domain of CD172a adjoined with an Fc linker sequence to the extracellular domain of human OX40L:

(SEQ ID NO: 12) ATGGAGCCCGCCGGCCCGGCCCCCGGCCGCCTCGGGCCGCTGC TCTGCCTGCTGCTCGCCGCGTCCTGCGCCTGGTCAGGAGTGGCG GGTGAGGAGGAGCTGCAGGTGATTCAGCCTGACAAGTCCGTGTTG GTTGCAGCTGGAGAGACAGCCACTCTGCGCTGCACTGCGACCTCT CTGATCCCTGTGGGGCCCATCCAGTGGTTCAGAGGAGCTGGACCA GGCCGGGAATTAATCTACAATCAAAAAGAAGGCCACTTCCCCCGG GTAACAACTGTTTCAGACCTCACAAAGAGAAACAACATGGACTTTT CCATCCGCATCGGTAACATCACCCCAGCAGATGCCGGCACCTACT ACTGTGTGAAGTTCCGGAAAGGGAGCCCCGATGACGTGGAGTTTA AGTCTGGAGCAGGCACTGAGCTGTCTGTGCGCGCCAAACCCTCTG CCCCCGTGGTATCGGGCCCTGCGGCGAGGGCCACACCTCAGCAC ACAGTGAGCTTCACCTGCGAGTCCCACGGCTTCTCACCCAGAGAC ATCACCCTGAAATGGTTCAAAAATGGGAATGAGCTCTCAGACTTCC AGACCAACGTGGACCCCGTAGGAGAGAGCGTGTCCTACAGCATCC ACAGCACAGCCAAGGTGGTGCTGACCCGCGAGGACGTTCACTCTC AAGTCATCTGCGAGGTGGCCCACGTCACCTTGCAGGGGGACCCT CTTCGTGGGACTGCCAACTTGTCTGAGACCATCCGAGTTCCACCC ACCTTGGAGGTTACTCAACAGCCCGTGAGGGCAGAGAACCAGGTG AATGTCACCTGCCAGGTGAGGAAGTTCTACCCCCAGAGACTACAG CTGACCTGGTTGGAGAATGGAAACGTGTCCCGGACAGAAACGGCC TCAACCGTTACAGAGAACAAGGATGGTACCTACAACTGGATGAGC TGGCTCCTGGTGAATGTATCTGCCCACAGGGATGATGTGAAGCTC ACCTGCCAGGTGGAGCATGACGGGCAGCCAGCGGTCAGCAAAAG CCATGACCTGAAGGTCTCAGCCCACCCGAAGGAGCAGGGCTCAAA TACCGCCGCTGAGAACACTGGATCTAATGAACGGAACATCTATTCT AAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTG GGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACC CTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGAT GTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGAC GGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACA GTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCA CCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCAAGGTGTCCAG CAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCAGCAACGCCAC CGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCCCTAGCC AGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTGA AGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACG GCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACA GCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGA GCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCAC GAAGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCC CTGGGCAAAATAGAGGGACGAATGGACCAGGTATCACATCGGTAT CCTCGAATTCAAAGTATCAAAGTACAATTTACCGAATATAAGAAG GAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCAT GAAGGTGCAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTA TCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAAGTCAACATTAG CCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAACTGAAGA AGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACA AAGACAAAGTCTACTTGAATGTGACCACTGACAATACCTCCCTGG ATGACTTCCATGTGAATGGCGGAGAACTGATTCTTATCCATCAAA ATCCTGGTGAATTCTGTGTCCTTTGA.

Such a sequence could be codon optimized to encode a protein with an amino acid sequence:

(SEQ ID NO: 13) M E P A G P A P G R L G P L L C L L L A A S C A W S G V A G E E E L Q V I Q P D K S V L V A A G E T A T L R C T A T S L I P V G P I Q W F R G A G P G R E L I Y N Q K E G H F P R V T T V S D L T K R N N M D F S I R I G N I T P A D A G T Y Y C V K F R K G S P D D V E F K S G A G T E L S V R A K P S A P V V S G P A A R A T P Q H T V S F T C E S H G F S P R D I T L K W F K N G N E L S D F Q T N V D P V G E S V S Y S I H S T A K V V L T R E D V H S Q V I C E V A H V T L Q G D P L R G T A N L S E T I R V P P T L E V T Q Q P V R A E N Q V N V T C Q V R K F Y P Q R L Q L T W L E N G N V S R T E T A S T V T E N K D G T Y N W M S W L L V N V S A H R D D V K L T C Q V E H D G Q P A V S K S H D L K V S A H P K E Q G S N T A A E N T G S N E R N I Y S K Y G P P C P S C P A P E F L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S Q E D P E V Q F N W Y V D G V E V H N A K T K P R E E Q F N S T Y R V V S V L T V L H Q D W L S G K E Y K C K V S S K G L P S S I E K T I S N A T G Q P R E P Q V Y T L P P S Q E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S R L T V D K S S W Q E G N V F S C S V M H E A L H N H Y T Q K S L S L S L G K I E G R M D Q V S H R Y P R I Q S I K V Q F T E Y K K E K G F I L T S Q K E D E I M K V Q N N S V I I N C D G F Y L I S L K G Y F S Q E V N I S L H Y Q K D E E P L F Q L K K V R S V N S L M V A S L T Y K D K V Y L N V T T D N T S L D D F H V N G G E L I L I H Q N P GE F C V L Stop.

Another example could include the extracellular domain of TMIGD2 adjoined with an Fc linker sequence to the extracellular domain of human OX40L:

(SEQ ID NO: 14) ATGGGGTCCCCGGGCATGGTGCTGGGCCTCCTGGTGCAGATCTG GGCCCTGCAAGAAGCCTCAAGCCTGAGCGTGCAGCAGGGGCCCA ACTTGCTGCAGGTGAGGCAGGGCAGTCAGGCGACCCTGGTCTGC CAGGTGGACCAGGCCACAGCCTGGGAACGGCTCCGTGTTAAGTG GACAAAGGATGGGGCCATCCTGTGTCAACCGTACATCACCAACGG CAGCCTCAGCCTGGGGGTCTGCGGGCCCCAGGGACGGCTCTCCT GGCAGGCACCCAGCCATCTCACCCTGCAGCTGGACCCTGTGAGC CTCAACCACAGCGGGGCGTACGTGTGCTGGGCGGCCGTAGAGAT TCCTGAGTTGGAGGAGGCTGAGGGCAACATAACAAGGCTCTTTGT GGACCCAGATGACCCCACACAGAACAGAAACCGGATCGCAAGCTT CCCAGGATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCC TGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCC CAAGGACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGT GGTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTG GTACGTGGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCA GAGAGGAACAGTTCAACAGCACCTACCGGGTGGTGTCTGTGCTGA CCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTACAAGTGCA AGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCATCA GCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTG CCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACA TGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGG GAGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCC AGTGCTGGACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGAC AGTGGACAAGAGCAGCTGGCAGGAAGGCAACGTGTTCAGCTGCA GCGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGTCCC TGAGCCTGTCCCTGGGCAAAATAGAGGGACGAATGGACCAGGTAT CACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCG AATATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAG GATGAAATCATGAAGGTGCAGAACAACTCAGTCATCATCAACTGT GATGGGTTTTATCTCATCTCCCTGAAGGGCTACTTCTCCCAGGAA GTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTC CAACTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCT CTGACTTACAAAGACAAAGTCTACTTGAATGTGACCACTGACAAT ACCTCCCTGGATGACTTCCATGTGAATGGCGGAGAACTGATTCTT ATCCATCAAAATCCTGGTGAATTCTGTGTCCTTTGA.

Such a sequence could be codon optimized to encode a protein with an amino acid sequence:

(SEQ ID NO: 15) M G S P G M V L G L L V Q I W A L Q E A S S L S V Q Q G P N L L Q V R Q G S Q A T L V C Q V D Q A T A W E R L R V K W T K D G A I L C Q P Y I T N G S L S L G V C G P Q G R L S W Q A P S H L T L Q L D P V S L N H S G A Y V C W A A V E I P E L E E A E G N I T R L F V D P D D P T Q N R N R I A S F P G   S K Y G P P C P S C P A P E F L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S Q E D P E V Q F N W Y V D G V E V H N A K T K P R E E Q F N S T Y R V V S V L T V L H Q D W L S G K E Y K C K V S S K G L P S S I E K T I S N A T G Q P R E P Q V Y T L P P S Q E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S R L T V D K S S W Q E G N V F S C S V M H E A L H N H Y T Q K S L S L S L G K I E G R M D Q V S H R Y P R I Q S I K V Q F    T E Y K K E K G F I L T S Q K E D E I M K V Q N N  S V I I N C D G F Y L I S L K G Y F S Q E V N I S L H Y Q K D E E P L F Q L K K V R S V N S L M V A S L T Y K D K V Y L N V T T D N T S L D D F H V N G G E L I L I H Q N P G E F C V L Stop 

In various embodiments, the chimeric protein may comprise an amino acid sequence having one or more amino acid mutations relative to any of the protein sequences described herein. In some embodiments, the one or more amino acid mutations may be independently selected from substitutions, insertions, deletions, and truncations.

In some embodiments, the amino acid mutations are amino acid substitutions, and may include conservative and/or non-conservative substitutions.

“Conservative substitutions” may be made, for instance, on the basis of similarity in polarity, charge, size, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the amino acid residues involved. The 20 naturally occurring amino acids can be grouped into the following six standard amino acid groups: (1) hydrophobic: Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr; Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

As used herein, “conservative substitutions” are defined as exchanges of an amino acid by another amino acid listed within the same group of the six standard amino acid groups shown above. For example, the exchange of Asp by Glu retains one negative charge in the so modified polypeptide. In addition, glycine and proline may be substituted for one another based on their ability to disrupt α-helices.

As used herein, “non-conservative substitutions” are defined as exchanges of an amino acid by another amino acid listed in a different group of the six standard amino acid groups (1) to (6) shown above.

In various embodiments, the substitutions may also include non-classical amino acids (e.g. selenocysteine, pyrrolysine, N-formylmethionine β-alanine, GABA and δ-Aminolevulinic acid, 4-aminobenzoic acid (PABA), D-isomers of the common amino acids, 2,4-diaminobutyric acid, α-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, γ-Abu, ϵ-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosme, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β methyl amino acids, C α-methyl amino acids, N α-methyl amino acids, and amino acid analogs in general).

Mutations may also be made to the nucleotide sequences of the chimeric proteins by reference to the genetic code, including taking into account codon degeneracy.

In various embodiments, the chimeric protein comprises a linker. In various embodiments, the linker may be derived from naturally-occurring multi-domain proteins or are empirical linkers as described, for example, in Chichili et al., (2013), Protein Sci. 22(2):153-167, Chen et al., (2013), Adv Drug Deliv Rev. 65(10):1357-1369, the entire contents of which are hereby incorporated by reference. In some embodiments, the linker may be designed using linker designing databases and computer programs such as those described in Chen et al., (2013), Adv Drug Deliv Rev. 65(10):1357-1369 and Crasto et. al., (2000), Protein Eng. 13(5):309-312, the entire contents of which are hereby incorporated by reference.

In some embodiments, the linker is a synthetic linker such as PEG.

In other embodiments, the linker is a polypeptide. In some embodiments, the linker is less than about 500 amino acids long, about 450 amino acids long, about 400 amino acids long, about 350 amino acids long, about 300 amino acids long, about 250 amino acids long, about 200 amino acids long, about 150 amino acids long, or about 100 amino acids long. For example, the linker may be less than about 100, about 95, about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, or about 2 amino acids long. In some embodiments, the linker is flexible. In another embodiment, the linker is rigid.

In various embodiments, the linker is substantially comprised of glycine and serine residues (e.g. about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 97% glycines and serines).

In various embodiments, the linker is a hinge region of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g. IgG1, IgG2, IgG3, and IgG4, and IgA1 and IgA2)). The hinge region, found in IgG, IgA, IgD, and IgE class antibodies, acts as a flexible spacer, allowing the Fab portion to move freely in space. In contrast to the constant regions, the hinge domains are structurally diverse, varying in both sequence and length among immunoglobulin classes and subclasses. For example, the length and flexibility of the hinge region varies among the IgG subclasses. The hinge region of IgG1 encompasses amino acids 216-231 and, because it is freely flexible, the Fab fragments can rotate about their axes of symmetry and move within a sphere centered at the first of two inter-heavy chain disulfide bridges. IgG2 has a shorter hinge than IgG1, with 12 amino acid residues and four disulfide bridges. The hinge region of IgG2 lacks a glycine residue, is relatively short, and contains a rigid poly-proline double helix, stabilized by extra inter-heavy chain disulfide bridges. These properties restrict the flexibility of the IgG2 molecule. IgG3 differs from the other subclasses by its unique extended hinge region (about four times as long as the IgG1 hinge), containing 62 amino acids (including 21 prolines and 11 cysteines), forming an inflexible poly-proline double helix. In IgG3, the Fab fragments are relatively far away from the Fc fragment, giving the molecule a greater flexibility. The elongated hinge in IgG3 is also responsible for its higher molecular weight compared to the other subclasses. The hinge region of IgG4 is shorter than that of IgG1 and its flexibility is intermediate between that of IgG1 and IgG2. The flexibility of the hinge regions reportedly decreases in the order IgG3>IgG1>IgG4>IgG2. In other embodiments, the linker may be derived from human IgG4 and contain one or more mutations to enhance dimerization (including S228P) or FcRn binding.

According to crystallographic studies, the immunoglobulin hinge region can be further subdivided functionally into three regions: the upper hinge region, the core region, and the lower hinge region. See Shin et al., 1992 Immunological Reviews 130:87. The upper hinge region includes amino acids from the carboxyl end of C_(H1) to the first residue in the hinge that restricts motion, generally the first cysteine residue that forms an interchain disulfide bond between the two heavy chains. The length of the upper hinge region correlates with the segmental flexibility of the antibody. The core hinge region contains the inter-heavy chain disulfide bridges, and the lower hinge region joins the amino terminal end of the C_(H2) domain and includes residues in C_(H2). Id. The core hinge region of wild-type human IgG1 contains the sequence Cys-Pro-Pro-Cys which, when dimerized by disulfide bond formation, results in a cyclic octapeptide believed to act as a pivot, thus conferring flexibility. In various embodiments, the present linker comprises, one, or two, or three of the upper hinge region, the core region, and the lower hinge region of any antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g. IgG1, IgG2, IgG3, and IgG4, and IgA1 and IgA2)). The hinge region may also contain one or more glycosylation sites, which include a number of structurally distinct types of sites for carbohydrate attachment. For example, IgA1 contains five glycosylation sites within a 17-amino-acid segment of the hinge region, conferring resistance of the hinge region polypeptide to intestinal proteases, considered an advantageous property for a secretory immunoglobulin. In various embodiments, the linker of the present invention comprises one or more glycosylation sites.

In various embodiments, the linker comprises an Fc domain of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g. IgG1, IgG2, IgG3, and IgG4, and IgA1 and IgA2)). In various embodiments, the linker comprises a hinge-CH2-CH3 Fc domain derived from a human IgG4 antibody. In various embodiments, the linker comprises a hinge-CH2-CH3 Fc domain derived from a human IgG1 antibody. In some embodiments, the Fc domain exhibits increased affinity for and enhanced binding to the neonatal Fc receptor (FcRn). In some embodiments, the Fc domain includes one or more mutations that increases the affinity and enhances binding to FcRn. Without wishing to be bound by theory, it is believed that increased affinity and enhanced binding to FcRn increases the in vivo half-life of the present chimeric proteins.

In some embodiments, the Fc domain linker contains one or more amino acid substitutions at amino acid residue 250, 252, 254, 256, 308, 309, 311, 428, 433 or 434 (in accordance with Kabat numbering), or equivalents thereof. In an embodiment, the amino acid substitution at amino acid residue 250 is a substitution with glutamine. In an embodiment, the amino acid substitution at amino acid residue 252 is a substitution with tyrosine, phenylalanine, tryptophan or threonine. In an embodiment, the amino acid substitution at amino acid residue 254 is a substitution with threonine. In an embodiment, the amino acid substitution at amino acid residue 256 is a substitution with serine, arginine, glutamine, glutamic acid, aspartic acid, or threonine. In an embodiment, the amino acid substitution at amino acid residue 308 is a substitution with threonine. In an embodiment, the amino acid substitution at amino acid residue 309 is a substitution with proline. In an embodiment, the amino acid substitution at amino acid residue 311 is a substitution with serine. In an embodiment, the amino acid substitution at amino acid residue 385 is a substitution with arginine, aspartic acid, serine, threonine, histidine, lysine, alanine or glycine. In an embodiment, the amino acid substitution at amino acid residue 386 is a substitution with threonine, proline, aspartic acid, serine, lysine, arginine, isoleucine, or methionine. In an embodiment, the amino acid substitution at amino acid residue 387 is a substitution with arginine, proline, histidine, serine, threonine, or alanine. In an embodiment, the amino acid substitution at amino acid residue 389 is a substitution with proline, serine or asparagine. In an embodiment, the amino acid substitution at amino acid residue 428 is a substitution with leucine. In an embodiment, the amino acid substitution at amino acid residue 433 is a substitution with arginine, serine, isoleucine, proline, or glutamine. In an embodiment, the amino acid substitution at amino acid residue 434 is a substitution with histidine, phenylalanine, or tyrosine.

In some embodiments, the Fc domain linker (e.g., comprising an IgG constant region) comprises one or more mutations such as substitutions at amino acid residue 252, 254, 256, 433, 434, or 436 (in accordance with Kabat numbering). In an embodiment, the IgG constant region includes a triple M252Y/S254T/T256E mutation or YTE mutation. In another embodiment, the IgG constant region includes a triple H433K/N434F/Y436H mutation or KFH mutation. In a further embodiment, the IgG constant region includes an YTE and KFH mutation in combination.

In some embodiments, the modified humanized antibodies of the invention comprise an IgG constant region that contains one or more mutations at amino acid residues 250, 253, 307, 310, 380, 428, 433, 434, and 435. Illustrative mutations include T250Q, M428L, T307A, E380A, I253A, H310A, M428L, H433K, N434A, N434F, N434S, and H435A. In an embodiment, the IgG constant region comprises a M428L/N434S mutation or LS mutation. In another embodiment, the IgG constant region comprises a T250Q/M428L mutation or QL mutation. In another embodiment, the IgG constant region comprises an N434A mutation. In another embodiment, the IgG constant region comprises a T307A/E380A/N434A mutation or AAA mutation. In another embodiment, the IgG constant region comprises an I253A/H310A/H435A mutation or IHH mutation. In another embodiment, the IgG constant region comprises a H433K/N434F mutation. In another embodiment, the IgG constant region comprises a M252Y/S254T/T256E and a H433K/N434F mutation in combination.

Additional exemplary mutations in the IgG constant region are described, for example, in Robbie, et al., Antimicrobial Agents and Chemotherapy (2013), 57(12):6147-6153, Dall'Acqua et al., JBC (2006), 281(33):23514-24, Dall'Acqua et al., Journal of Immunology (2002), 169:5171-80, Ko et al. Nature (2014) 514:642-645, Grevys et al. Journal of Immunology. (2015), 194(11):5497-508, and U.S. Pat. No. 7,083,784, the entire contents of which are hereby incorporated by reference.

In some embodiments, the linker has the amino acid sequence of SEQ ID NO: 70, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto. In various embodiments, mutations are made to SEQ ID No: 70 to increase stability and/or half-life. For instance, in some embodiments, the linker has the amino acid sequence of SEQ ID NO: 71 or 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto. An illustrative Fc stabilizing mutant is S228P. Illustrative Fc half-life extending mutants are T250Q, M428L, V308T, L309P, and Q311S and the present linkers may comprise 1, or 2, or 3, or 4, or 5 of these mutants.

Further, one or more joining linkers may be employed to connect the present IgG linkers (e.g. one or SEQ ID NOs: 70, 71, or 71, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto) and the extracellular domains. For example, any one of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof may connect an extracellular domain as described herein and a linker as described herein. Optionally, any one of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof are displaced between an extracellular domain as described herein and a linker as described herein.

Additional illustrative linkers include, but are not limited to, linkers having the sequence LE, GGGGS (SEQ ID NO: 23), (GGGGS)_(n) (n=1-4), (Gly)₈, (Gly)₆, (EAAAK)_(n) (n=1-3) (SEQ ID NO: 24), A(EAAAK)_(n)A (n=2-5) (SEQ ID NO: 25), AEAAAKEAAAKA (SEQ ID NO: 26), A(EAAAK)₄ALEA(EAAAK)₄A (SEQ ID NO: 27), PAPAP (SEQ ID NO: 28), KESGSVSSEQLAQFRSLD (SEQ ID NO: 29), EGKSSGSGSESKST (SEQ ID NO: 30), GSAGSAAGSGEF (SEQ ID NO:31), and (XP)_(n), with X designating any amino acid, e.g., Ala, Lys, or Glu.

In various embodiments, the linker may be functional. For example, without limitation, the linker may function to improve the folding and/or stability, improve the expression, improve the pharmacokinetics, and/or improve the bioactivity of the present chimeric protein. In another example, the linker may function to target the chimeric protein to a particular cell type or location.

In various embodiments, the present chimeric proteins are capable of, and can be used in methods comprising, promoting immune activation (e.g. against tumors). In various embodiments, the present chimeric proteins are capable of, and can be used in methods comprising, suppressing immune inhibition (e.g. that allows tumors to survive). In various embodiments, the present chimeric proteins provide improved immune activation and/or improved suppression of immune inhibition due to the proximity of signaling that is provided by the chimeric nature of the constructs.

In various embodiments, the present chimeric proteins are capable of, or can be used in methods comprising, modulating the amplitude of an immune response, e.g. modulating the level of effector output. In some embodiments, e.g. when used for the treatment of cancer, the present chimeric proteins alter the extent of immune stimulation as compared to immune inhibition to increase the amplitude of a T cell response, including, without limitation, stimulating increased levels of cytokine production, proliferation or target killing potential.

In various embodiments the present chimeric proteins, in some embodiments are capable of, or find use in methods involving, masking an inhibitory ligand on the surface of a tumor cell and replacing that immune inhibitory ligand with an immune stimulatory ligand (see, e.g. FIG. 4). For example, a chimeric protein construct comprising (i) the extracellular domain of PD-1 and (ii) extracellular domain of OX40L, allows for the disruption of an inhibitory PD-L1 signal and replacing it with a stimulating OX40L. Accordingly, the present chimeric proteins, in some embodiments are capable of, or find use in methods involving, reducing or eliminating an inhibitory immune signal and/or increasing or activating an immune stimulatory signal. For example, a tumor cell bearing an inhibitory signal (and thus evading an immune response) may be substituted for a positive signal binding on a T cell that can then attack a tumor cell. Accordingly, in some embodiments, an inhibitory immune signal is masked by the present constructs and a stimulatory immune signal is activated. Such beneficial properties are enhanced by the single construct approach of the present chimeric proteins. For instance, the signal replacement can be effected nearly simultaneously and the signal replacement is tailored to be local at a site of clinical importance (e.g. the tumor microenvironment). Further embodiments apply the same principle to other chimeric protein constructs, such as, for example, (i) the extracellular domain of PD-1 and (ii) extracellular domain of GITRL; (i) the extracellular domain of BTLA and (ii) extracellular domain of OX40L; (i) the extracellular domain of TIGIT and (ii) extracellular domain of OX40L; (i) the extracellular domain of TIM3 and (ii) extracellular domain of OX40L; and (i) the extracellular domain of CD172a and (ii) extracellular domain of CD40L; and (i) the extracellular domain of CD115 and (ii) extracellular domain of CD40L; and (i) the extracellular domain of TIM3 and (ii) extracellular domain of OX40L; and (i) the extracellular domain of TIGIT and (ii) extracellular domain of OX40L; among others.

In various embodiments, the present chimeric proteins are capable of, or find use in methods comprising, stimulating or enhancing the binding of immune stimulatory receptor/ligand pairs. Illustrative T cell costimulatory receptors and their ligands include OX-40:OX40-L, CD27:CD70, CD30:CD30-L, CD40:CD40-L; CD137:CD137-L, HVEM:LIGHT, GITR:GITR-L, TNFRSF25:TL1A, DR5:TRAIL, and BTLA:HVEM. In various embodiments, the present chimeric proteins are capable of, or find use in methods comprising, inhibiting or reducing the binding of immune inhibitory receptor/ligand pairs. Illustrative T cell coinhibitory receptors and their ligands include, for example, CTLA-4:CD80/CD86, PD-1:PD-L1/PD-L2, BTLA:HVEM, TIM-3:galectin-9/phosphatidylserine, TIGIT/CD155 or CD112, VISTA/VSIG8, CD172a/CD47, B7H3R/B7H3, B7H4R/B7H4, CD244/CD48, TMIGD2/HHLA2, among others.

In various embodiments, the present chimeric protein blocks, reduces and/or inhibits PD-1 and PD-L1 or PD-L2 and/or the binding of PD-1 with PD-L1 or PD-L2. In various embodiments, the present chimeric protein blocks, reduces and/or inhibits the activity of CTLA-4 and/or the binding of CTLA-4 with one or more of AP2M1, CD80, CD86, SHP-2, and PPP2R5A. In various embodiments, the present chimeric protein increases and/or stimulates GITR and/or the binding of GITR with one or more of GITR ligand. In various embodiments, the present chimeric protein increases and/or stimulates OX40 and/or the binding of OX40 with one or more of OX40 ligand.

In other embodiments, the present chimeric proteins are capable of, or find use in methods involving, enhancing, restoring, promoting and/or stimulating immune modulation. In some embodiments, the present chimeric proteins described herein, restore, promote and/or stimulate the activity or activation of one or more immune cells against tumor cells including, but not limited to: T cells, cytotoxic T lymphocytes, T helper cells, natural killer (NK) cells, natural killer T (NKT) cells, anti-tumor macrophages (e.g. M1 macrophages), B cells, and dendritic cells. In some embodiments, the present chimeric proteins enhance, restore, promote and/or stimulate the activity and/or activation of T cells, including, by way of a non-limiting example, activating and/or stimulating one or more T-cell intrinsic signals, including a pro-survival signal; an autocrine or paracrine growth signal; a p38 MAPK-, ERK-, STAT-, JAK-, AKT- or PI3K-mediated signal; an anti-apoptotic signal; and/or a signal promoting and/or necessary for one or more of: proinflammatory cytokine production or T cell migration or T cell tumor infiltration.

In some embodiments, the present chimeric proteins are capable of, or find use in methods involving, causing an increase of one or more of T cells (including without limitation cytotoxic T lymphocytes, T helper cells, natural killer T (NKT) cells), B cells, natural killer (NK) cells, natural killer T (NKT) cells, dendritic cells, monocytes, and macrophages (e.g. one or more of M1 and M2) into a tumor or the tumor microenvironment. In some embodiments, the present chimeric proteins are capable of, or find use in methods involving, inhibiting and/or causing a decrease in recruitment of immunosuppressive cells (e.g. myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumor associated neutrophils (TANs), M2 macrophages, and tumor associated macrophages (TAMs)) to the tumor and/or tumor microenvironment (TME). In some embodiments, the present therapies may alter the ratio of M1 versus M2 macrophages in the tumor site and/or TME to favor M1 macrophages.

In various embodiments, the present chimeric proteins are capable of, and can be used in methods comprising, inhibiting and/or reducing T cell inactivation and/or immune tolerance to a tumor, comprising administering an effective amount of a chimeric protein described herein to a subject. In some embodiments, the present chimeric proteins are able to increase the serum levels of various cytokines including, but not limited to, one or more of IFNγ, TNFα, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, and IL-22. In some embodiments, the present chimeric proteins are capable of enhancing IL-2, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-22, TNFα or IFNγ in the serum of a treated subject (see, e.g. FIG. 11, panel J). Detection of such a cytokine response may provide a method to determine the optimal dosing regimen for the indicated chimeric fusion protein (see, e.g. FIG. 11, panel K).

In various embodiments, the present chimeric proteins inhibit, block and/or reduce cell death of an anti-tumor CD8+ and/or CD4+ T cell; or stimulate, induce, and/or increase cell death of a pro-tumor T cell. T cell exhaustion is a state of T cell dysfunction characterized by progressive loss of proliferative and effector functions, culminating in clonal deletion. Accordingly, a pro-tumor T cell refers to a state of T cell dysfunction that arises during many chronic infections and cancer. This dysfunction is defined by poor proliferative and/or effector functions, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. In addition, an anti-tumor CD8+ and/or CD4+ T cell refers to T cells that can mount an immune response to a tumor. Illustrative pro-tumor T cells include, but are not limited to, Tregs, CD4+ and/or CD8+ T cells expressing one or more checkpoint inhibitory receptors, Th2 cells and Th17 cells. Checkpoint inhibitory receptors refers to receptors (e.g. CTLA-4, B7-H3, B7-H4, TIM-3) expressed on immune cells that prevent or inhibit uncontrolled immune responses.

In various embodiments, the present chimeric proteins are capable of, and can be used in methods comprising, increasing a ratio of effector T cells to regulatory T cells. Illustrative effector T cells include ICOS⁺ effector T cells; cytotoxic T cells (e.g. αβ TCR, CD3⁺, CD8⁺, CD45RO⁺); CD4⁺ effector T cells (e.g. αβ TCR, CD3⁺, CD4⁺, CCR7⁺, CD62Lhi, IL⁻7R/CD127⁺); CD8⁺ effector T cells (e.g. αβ TCR, CD3⁺, CD8⁺, CCR7⁺, CD62Lhi, IL⁻7R/CD127⁺); effector memory T cells (e.g. CD62Llow, CD44⁺, TCR, CD3⁺≤, IL⁻7R/CD127⁺, IL-15R⁺, CCR7low); central memory T cells (e.g. CCR7⁺, CD62L⁺, CD27⁺; or CCR7hi, CD44⁺, CD62Lhi, TCR, CD3⁺, IL-7R/CD127⁺, IL-15R⁺); CD62L⁺ effector T cells; CD8⁺ effector memory T cells (TEM) including early effector memory T cells (CD27⁺ CD62L⁻) and late effector memory T cells (CD27⁻CD62L⁻) (TemE and TemL, respectively); CD127(⁺)CD25(low/−) effector T cells; CD127(⁻)CD25(⁻) effector T cells; CD8⁺ stem cell memory effector cells (TSCM) (e.g. CD44(low)CD62L(high)CD122(high)sca(⁺)); TH1 effector T-cells (e.g. CXCR3⁺, CXCR6⁺ and CCR5⁺; or αβ TCR, CD3⁺, CD4⁺, IL-12R⁺, IFNγR⁺, CXCR3⁺), TH2 effector T cells (e.g. CCR3⁺, CCR4⁺ and CCR8⁺; or αβ TCR, CD3⁺, CD4⁺, IL-4R⁺, IL-33R⁺, CCR4⁺, IL-17RB⁺, CRTH2⁺); TH9 effector T cells (e.g. αβ TCR, CD3⁺, CD4⁺); TH17 effector T cells (e.g. αβ TCR, CD3⁺, CD4⁺, IL-23R⁺, CCR6⁺, IL-1R⁺); CD4⁺CD45RO⁺CCR7⁺ effector T cells, CD4⁺CD45RO⁺CCR7(⁻) effector T cells; and effector T cells secreting IL-2, IL-4 and/or IFN-γ. Illustrative regulatory T cells include ICOS⁺ regulatory T cells, CD4⁺CD25⁺FOXP3⁺ regulatory T cells, CD4⁺CD25⁺ regulatory T cells, CD4⁺CD25⁻ regulatory T cells, CD4⁺CD25high regulatory T cells, TIM-3⁺PD-1⁺ regulatory T cells, lymphocyte activation gene-3 (LAG-3)⁺ regulatory T cells, CTLA-4/CD152⁺ regulatory T cells, neuropilin-1 (Nrp-1)⁺ regulatory T cells, CCR4⁺CCR8⁺ regulatory T cells, CD62L (L-selectin)⁺ regulatory T cells, CD45RBlow regulatory T cells, CD127low regulatory T cells, LRRC32/GARP⁺ regulatory T cells, CD39⁺ regulatory T cells, GITR⁺ regulatory T cells, LAP⁺ regulatory T cells, 1B11⁺ regulatory T cells, BTLA⁺ regulatory T cells, type 1 regulatory T cells (Tr1 cells), T helper type 3 (Th3) cells, regulatory cell of natural killer T cell phenotype (NKTregs), CD8⁺ regulatory T cells, CD8⁺CD28⁻regulatory T cells and/or regulatory T-cells secreting IL-10, IL-35, TGF-β, TNF-α, Galectin-1, IFN-γ and/or MCP1.

In various embodiments, the present chimeric proteins are capable of, and can be used in methods comprising, transiently stimulating effector T cells for no longer than about 12 hours, about 24 hours, about 48 hours, about 72 hours or about 96 hours or about 1 week or about 2 weeks. In various embodiments, the present chimeric proteins are capable of, and can be used in methods comprising, transiently depleting or inhibiting regulatory T cells for no longer than about 12 hours, about 24 hours, about 48 hours, about 72 hours or about 96 hours or about 1 week or about 2 weeks. In various embodiments, the transient stimulation of effector T cells and/or transient depletion or inhibition of regulatory T cells occurs substantially in a patient's bloodstream or in a particular tissue/location including lymphoid tissues such as for example, the bone marrow, lymph-node, spleen, thymus, mucosa-associated lymphoid tissue (MALT), non-lymphoid tissues, or in the tumor microenvironment.

In various embodiments, the present chimeric proteins provide advantages including, without limitation, ease of use and ease of production. This is because two distinct immunotherapy agents are combined into a single product which allows for a single manufacturing process instead of two independent manufacturing processes. In addition, administration of a single agent instead of two separate agents allows for easier administration and greater patient compliance. Further, in contrast to, for example, monoclonal antibodies, which are large multimeric proteins containing numerous disulfide bonds and post-translational modifications such as glycosylation, the present chimeric proteins are easier and more cost effective to manufacture.

In various embodiments, the present chimeric protein is produceable in a mammalian host cell as a secretable and fully functional single polypeptide chain (see, e.g., FIG. 13, panel A, FIG. 17, panels E-H, FIG. 17, panels N-S).

In various embodiments, the present chimeric protein unexpectedly provides binding of the extracellular domain components to their respective binding partners with slow off rates (Kd or K_(off)). In some embodiments, this provides an unexpectedly long interaction of the receptor to ligand and vice versa. Such an effect allows for a sustained negative signal masking effect (see, e.g., FIG. 14, FIG. 17, panels I-M). Further, in some embodiments, this delivers a longer positive signal effect, e.g. to allow an effector cell to be adequately stimulated for an anti-tumor effect. For example, the present chimeric protein, e.g. via the long off rate binding allows sufficient signal transmission to provide T cell proliferation and allow for anti-tumor attack. By way of further example, the present chimeric protein, e.g. via the long off rate binding allows sufficient signal transmission to provide release of stimulatory signals, such as, for example, cytokines Also. The stable synapse of cells promoted by the present agents (e.g. a tumor cell bearing negative signals and a T cell which could attack the tumor) provides spatial orientation to favor tumor reduction—such as positioning the T cells to attack tumor cells and/or sterically preventing the tumor cell from delivering negative signals, including negative signals beyond those masked by the chimeric protein of the invention.

In some embodiments, this provides longer on-target (e.g. intra-tumoral) half-life (t_(1/2)) as compared to serum t_(1/2) of the chimeric proteins. Such properties could have the combined advantage of reducing off-target toxicities associated with systemic distribution of the chimeric proteins (see, e.g., FIG. 14, panels M-O).

Further, in various embodiments, the present chimeric proteins provide synergistic therapeutic effects as it allows for improved site-specific interplay of two immunotherapy agents. In some embodiments, the present chimeric proteins provide the potential for reducing off-site and/or systemic toxicity.

Diseases; Methods of Treatment, and Patient Selections

In various embodiments, the present invention pertains to cancers and/or tumors; for example, the treatment or prevention of cancers and/or tumors. As described elsewhere herein, the treatment of cancer may involve in various embodiments, modulating the immune system with the present chimeric proteins to favor immune stimulation over immune inhibition.

Cancers or tumors refer to an uncontrolled growth of cells and/or abnormal increased cell survival and/or inhibition of apoptosis which interferes with the normal functioning of the bodily organs and systems. Included are benign and malignant cancers, polyps, hyperplasia, as well as dormant tumors or micrometastases. Also, included are cells having abnormal proliferation that is not impeded by the immune system (e.g. virus infected cells). The cancer may be a primary cancer or a metastatic cancer. The primary cancer may be an area of cancer cells at an originating site that becomes clinically detectable, and may be a primary tumor. In contrast, the metastatic cancer may be the spread of a disease from one organ or part to another non-adjacent organ or part. The metastatic cancer may be caused by a cancer cell that acquires the ability to penetrate and infiltrate surrounding normal tissues in a local area, forming a new tumor, which may be a local metastasis. The cancer may also be caused by a cancer cell that acquires the ability to penetrate the walls of lymphatic and/or blood vessels, after which the cancer cell is able to circulate through the bloodstream (thereby being a circulating tumor cell) to other sites and tissues in the body. The cancer may be due to a process such as lymphatic or hematogeneous spread. The cancer may also be caused by a tumor cell that comes to rest at another site, re-penetrates through the vessel or walls, continues to multiply, and eventually forms another clinically detectable tumor. The cancer may be this new tumor, which may be a metastatic (or secondary) tumor.

The cancer may be caused by tumor cells that have metastasized, which may be a secondary or metastatic tumor. The cells of the tumor may be like those in the original tumor. As an example, if a breast cancer or colon cancer metastasizes to the liver, the secondary tumor, while present in the liver, is made up of abnormal breast or colon cells, not of abnormal liver cells. The tumor in the liver may thus be a metastatic breast cancer or a metastatic colon cancer, not liver cancer.

The cancer may have an origin from any tissue. The cancer may originate from melanoma, colon, breast, or prostate, and thus may be made up of cells that were originally skin, colon, breast, or prostate, respectively. The cancer may also be a hematological malignancy, which may be leukemia or lymphoma. The cancer may invade a tissue such as liver, lung, bladder, or intestinal.

Representative cancers and/or tumors of the present invention include, but are not limited to, a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

In some embodiments, the chimeric protein is used to treat a subject that has a treatment-refractory cancer. In some embodiments, the chimeric protein is used to treat a subject that is refractory to one or more immune-modulating agents. For example, in some embodiments, the chimeric protein is used to treat a subject that presents no response to treatment, or even progress, after 12 weeks or so of treatment. For instance, in some embodiments, the subject is refractory to a PD-1 and/or PD-L1 and/or PD-L2 agent, including, for example, nivolumab (ONO-4538/BMS-936558, MDX1106, OPDIVO, BRISTOL MYERS SQUIBB), pembrolizumab (KEYTRUDA, MERCK), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559 (BRISTOL MYERS SQUIBB), Ibrutinib (PHARMACYCLICS/ABBVIE), atezolizumab (TECENTRIQ, GENENTECH), and/or MPDL328OA (ROCHE)-refractory patients. For instance, in some embodiments, the subject is refractory to an anti-CTLA-4 agent, e.g. ipilimumab (YERVOY)-refractory patients (e.g. melanoma patients). Accordingly, in various embodiments the present invention provides methods of cancer treatment that rescue patients that are non-responsive to various therapies, including monotherapy of one or more immune-modulating agents.

In some embodiments, the present methods provide treatment with the chimeric protein in a patient who is refractory to an additional agent, such “additional agents” being described elsewhere herein, inclusive, without limitation, of the various chemotherapeutic agents described herein.

In some aspects, the present chimeric agents are used to eliminate intracellular pathogens. In some aspects, the present chimeric agents are used to treat one or more infections. In some embodiments, the present chimeric proteins are used in methods of treating viral infections (including, for example, HIV and HCV), parasitic infections (including, for example, malaria), and bacterial infections. In various embodiments, the infections induce immunosuppression. For example, HIV infections often result in immunosuppression in the infected subjects. Accordingly, as described elsewhere herein, the treatment of such infections may involve, in various embodiments, modulating the immune system with the present chimeric proteins to favor immune stimulation over immune inhibition. Alternatively, the present invention provides methods for treating infections that induce immunoactivation. For example, intestinal helminth infections have been associated with chronic immune activation. In these embodiments, the treatment of such infections may involve modulating the immune system with the present chimeric proteins to favor immune inhibition over immune stimulation.

In various embodiments, the present invention provides methods of treating viral infections including, without limitation, acute or chronic viral infections, for example, of the respiratory tract, of papilloma virus infections, of herpes simplex virus (HSV) infection, of human immunodeficiency virus (HIV) infection, and of viral infection of internal organs such as infection with hepatitis viruses. In some embodiments, the viral infection is caused by a virus of family Flaviviridae. In some embodiments, the virus of family Flaviviridae is selected from Yellow Fever Virus, West Nile virus, Dengue virus, Japanese Encephalitis Virus, St. Louis Encephalitis Virus, and Hepatitis C Virus. In other embodiments, the viral infection is caused by a virus of family Picornaviridae, e.g., poliovirus, rhinovirus, coxsackievirus. In other embodiments, the viral infection is caused by a member of Orthomyxoviridae, e.g., an influenza virus. In other embodiments, the viral infection is caused by a member of Retroviridae, e.g., a lentivirus. In other embodiments, the viral infection is caused by a member of Paramyxoviridae, e.g., respiratory syncytial virus, a human parainfluenza virus, rubulavirus (e.g., mumps virus), measles virus, and human metapneumovirus. In other embodiments, the viral infection is caused by a member of Bunyaviridae, e.g., hantavirus. In other embodiments, the viral infection is caused by a member of Reoviridae, e.g., a rotavirus.

In various embodiments, the present invention provides methods of treating parasitic infections such as protozoan or helminths infections. In some embodiments, the parasitic infection is by a protozoan parasite. In some embodiments, the oritiziab parasite is selected from intestinal protozoa, tissue protozoa, or blood protozoa. Illustrative protozoan parasites include, but are not limited to, Entamoeba hystolytica, Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense, Trypanosomatida rhodesiense, Trypanosomatida crusi, Leishmania mexicana, Leishmania braziliensis, Leishmania tropica, Leishmania donovani, Toxoplasma gondii, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum, Trichomonas vaginalis, and Histomonas meleagridis. In some embodiments, the parasitic infection is by a helminthic parasite such as nematodes (e.g., Adenophorea). In some embodiments, the parasite is selected from Secementea (e.g., Trichuris trichiura, Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Wuchereria bancrofti, Dracunculus medinensis). In some embodiments, the parasite is selected from trematodes (e.g. blood flukes, liver flukes, intestinal flukes, and lung flukes). In some embodiments, the parasite is selected from: Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica, Fasciola gigantica, Heterophyes heterophyes, Paragonimus westermani. In some embodiments, the parasite is selected from cestodes (e.g., Taenia solium, Taenia saginata, Hymenolepis nana, Echinococcus granulosus).

In various embodiments, the present invention provides methods of treating bacterial infections. In various embodiments, the bacterial infection is by a gram-positive bacteria, gram-negative bacteria, aerobic and/or anaerobic bacteria. In various embodiments, the bacteria is selected from, but not limited to, Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms. In some embodiments, the bacteria is selected from, but not limited to, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

In some aspects, the present chimeric agents are used to treat one or more autoimmune diseases or disorders. In various embodiments, the treatment of an autoimmune disease or disorder may involve modulating the immune system with the present chimeric proteins to favor immune inhibition over immune stimulation. Illustrative autoimmune diseases or disorders treatable with the present chimeric proteins include those in which the body's own antigens become targets for an immune response, such as, for example, rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus, ankylosing spondylitis, Sjögren's syndrome, inflammatory bowel diseases (e.g. colitis ulcerosa, Crohn's disease), multiple sclerosis, sarcoidosis, psoriasis, Grave's disease, Hashimoto's thyroiditis, psoriasis, hypersensitivity reactions (e.g., allergies, hay fever, asthma, and acute edema cause type I hypersensitivity reactions), and vasculitis.

In still another other aspect, the present invention is directed toward methods of treating and preventing T cell-mediated diseases and disorders, such as, but not limited to diseases or disorders described elsewhere herein and inflammatory disease or disorder, graft-versus-host disease (GVHD), transplant rejection, and T cell proliferative disorder. Specific examples of type I ECD domains with utility in this method of use include but are not limited to: TNFRSF1b, BTNL2, PD-L1, PD-L2, CTLA-4, B7-H3, B7-H4, CD40, OX40, CD137, among others.

In some aspects, the present chimeric agents are used in methods of activating a T cell, e.g. via the extracellular domain having an immune stimulatory signal.

In some aspects, the present chimeric agents are used in methods of preventing the cellular transmission of an immunosuppressive signal.

Combination Therapies and Conjugation

In some embodiments, the invention provides for chimeric proteins and methods that further comprise administering an additional agent to a subject. In some embodiments, the invention pertains to co-administration and/or co-formulation. Any of the compositions described herein may be co-formulated and/or co-administered.

In some embodiments, any chimeric protein described herein acts synergistically when co-administered with another agent and is administered at doses that are lower than the doses commonly employed when such agents are used as monotherapy. In various embodiments, any agent referenced herein may be used in combination with any of the chimeric proteins described herein.

In some embodiments, inclusive of, without limitation, cancer applications, the present invention pertains to chemotherapeutic agents as additional agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as minoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE. vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); lapatinib (TYKERB); inhibitors of PKC-α, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation and pharmaceutically acceptable salts, acids or derivatives of any of the above. In addition, the methods of treatment can further include the use of radiation. In addition, the methods of treatment can further include the use of photodynamic therapy.

In various embodiments, inclusive of, without limitation, cancer applications, the present additional agent is one or more immune-modulating agents selected from an agent that blocks, reduces and/or inhibits PD-1 and PD-L1 or PD-L2 and/or the binding of PD-1 with PD-L1 or PD-L2 (by way of non-limiting example, one or more of nivolumab (ONO-4538/BMS-936558, MDX1106, OPDIVO, BRISTOL MYERS SQUIBB), pembrolizumab (KEYTRUDA, Merck), pidilizumab (CT-011, CURE TECH), MK-3475 (MERCK), BMS 936559 (BRISTOL MYERS SQUIBB), atezolizumab (TECENTRIQ, GENENTECH), MPDL328OA (ROCHE)), an agent that increases and/or stimulates CD137 (4-1BB) and/or the binding of CD137 (4-1BB) with one or more of 4-1BB ligand (by way of non-limiting example, urelumab (BMS-663513 and anti-4-1BB antibody), and an agent that blocks, reduces and/or inhibits the activity of CTLA-4 and/or the binding of CTLA-4 with one or more of AP2M1, CD80, CD86, SHP-2, and PPP2R5A and/or the binding of OX40 with OX40L (by way of non-limiting example GBR 830 (GLENMARK), MEDI6469 (MEDIMMUNE).

In some embodiments, inclusive of, without limitation, infectious disease applications, the present invention pertains to anti-infectives as additional agents. In some embodiments, the anti-infective is an anti-viral agent including, but not limited to, Abacavir, Acyclovir, Adefovir, Amprenavir, Atazanavir, Cidofovir, Darunavir, Delavirdine, Didanosine, Docosanol, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Etravirine, Famciclovir, and Foscarnet. In some embodiments, the anti-infective is an anti-bacterial agent including, but not limited to, cephalosporin antibiotics (cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole); fluoroquinolone antibiotics (cipro, Levaquin, floxin, tequin, avelox, and norflox); tetracycline antibiotics (tetracycline, minocycline, oxytetracycline, and doxycycline); penicillin antibiotics (amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, vancomycin, and methicillin); monobactam antibiotics (aztreonam); and carbapenem antibiotics (ertapenem, doripenem, imipenem/cilastatin, and meropenem). In some embodiments, the anti-infectives include anti-malarial agents (e.g., chloroquine, quinine, mefloquine, primaquine, doxycycline, artemether/lumefantrine, atovaquone/proguanil and sulfadoxine/pyrimethamine), metronidazole, tinidazole, ivermectin, pyrantel pamoate, and albendazole.

In some embodiments, inclusive, without limitation, of autoimmune applications, the additional agent is an immunosuppressive agent. In some embodiments, the immunosuppressive agent is an anti-inflammatory agent such as a steroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent (NSAID). Steroids, particularly the adrenal corticosteroids and their synthetic analogues, are well known in the art. Examples of corticosteroids useful in the present invention include, without limitation, hydroxyltriamcinolone, alpha-methyl dexamethasone, beta-methyl betamethasone, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate. (NSAIDS) that may be used in the present invention, include but are not limited to, salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, and indomethacin. In some embodiments, the immunosupressive agent may be cytostatics such as alkylating agents, antimetabolites (e.g., azathioprine, methotrexate), cytotoxic antibiotics, antibodies (e.g., basiliximab, daclizumab, and muromonab), anti-immunophilins (e.g., cyclosporine, tacrolimus, sirolimus), inteferons, opioids, TNF binding proteins, mycophenolates, and small biological agents (e.g., fingolimod, myriocin).

In some embodiments, the chimeric proteins (and/or additional agents) described herein, include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the composition such that covalent attachment does not prevent the activity of the composition. For example, but not by way of limitation, derivatives include composition that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of turicamycin, etc. Additionally, the derivative can contain one or more non-classical amino acids. In still other embodiments, the chimeric proteins (and/or additional agents) described herein further comprise a cytotoxic agent, comprising, in illustrative embodiments, a toxin, a chemotherapeutic agent, a radioisotope, and an agent that causes apoptosis or cell death. Such agents may be conjugated to a composition described herein.

The chimeric proteins (and/or additional agents) described herein may thus be modified post-translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

Formulations

The chimeric proteins (and/or additional agents) described herein can possess a sufficiently basic functional group, which can react with an inorganic or organic acid, or a carboxyl group, which can react with an inorganic or organic base, to form a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

In some embodiments, the compositions described herein are in the form of a pharmaceutically acceptable salt.

Further, any chimeric protein (and/or additional agents) described herein can be administered to a subject as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration. Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.

In some embodiments, the compositions described herein are resuspended in a saline buffer (including, without limitation TBS, PBS, and the like).

In various embodiments, the chimeric proteins may by conjugated and/or fused with another agent to extend half-life or otherwise improve pharmacodynamic and pharmacokinetic properties. In some embodiments, the chimeric proteins may be fused or conjugated with one or more of PEG, XTEN (e.g., as rPEG), polysialic acid (POLYXEN), albumin (e.g., human serum albumin or HAS), elastin-like protein (ELP), PAS, HAP, GLK, CTP, transferrin, and the like. In various embodiments, each of the individual chimeric proteins is fused to one or more of the agents described in BioDrugs (2015) 29:215-239, the entire contents of which are hereby incorporated by reference.

Administration, Dosing, and Treatment Regimens

The present invention includes the described chimeric protein (and/or additional agents) in various formulations. Any chimeric protein (and/or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. DNA or RNA constructs encoding the protein sequences may also be used. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

Where necessary, the formulations comprising the chimeric protein (and/or additional agents) can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.

The formulations comprising the chimeric protein (and/or additional agents) of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art)

In one embodiment, any chimeric protein (and/or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. In some embodiments, the administering is effected orally or by parenteral injection. In most instances, administration results in the release of any agent described herein into the bloodstream.

Any chimeric protein (and/or additional agents) described herein can be administered orally. Such chimeric proteins (and/or additional agents) can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer.

In specific embodiments, it may be desirable to administer locally to the area in need of treatment. In one embodiment, for instance in the treatment of cancer, the chimeric protein (and/or additional agents) are administered in the tumor microenvironment (e.g. cells, molecules, extracellular matrix and/or blood vessels that surround and/or feed a tumor cell, inclusive of, for example, tumor vasculature; tumor-infiltrating lymphocytes; fibroblast reticular cells; endothelial progenitor cells (EPC); cancer-associated fibroblasts; pericytes; other stromal cells; components of the extracellular matrix (ECM); dendritic cells; antigen presenting cells; T-cells; regulatory T cells; macrophages; neutrophils; and other immune cells located proximal to a tumor) or lymph node and/or targeted to the tumor microenvironment or lymph node. In various embodiments, for instance in the treatment of cancer, the chimeric protein (and/or additional agents) are administered intratumorally.

In the various embodiments, the present chimeric protein allows for a dual effect that provides less side effects than are seen in conventional immunotherapy (e.g. treatments with one or more of OPDIVO, KEYTRUDA, YERVOY, and TECENTRIQ). For example, the present chimeric proteins reduce or prevent commonly observed immune-related adverse events that affect various tissues and organs including the skin, the gastrointestinal tract, the kidneys, peripheral and central nervous system, liver, lymph nodes, eyes, pancreas, and the endocrine system; such as hypophysitis, colitis, hepatitis, pneumonitis, rash, and rheumatic disease. Further, the present local administration, e.g. intratumorally, obviate adverse event seen with standard systemic administration, e.g. IV infusions, as are used with conventional immunotherapy (e.g. treatments with one or more of OPDIVO, KEYTRUDA, YERVOY, and TECENTRIQ).

Dosage forms suitable for parenteral administration (e.g. intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.

The dosage of any chimeric protein (and/or additional agents) described herein as well as the dosing schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject's general health, and the administering physician's discretion. Any chimeric protein described herein, can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of an additional agent, to a subject in need thereof. In various embodiments any chimeric protein and additional agent described herein are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.

The dosage of any chimeric protein (and/or additional agents) described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.

For administration of any chimeric protein (and/or additional agents) described herein by parenteral injection, the dosage is normally 0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day. Injections may be given up to four times daily. Generally, when orally or parenterally administered, the dosage of any agent described herein is normally 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day. A dosage of up to 3000 mg per day can be administered.

In another embodiment, delivery can be in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

Any chimeric protein (and/or additional agents) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).

In another embodiment, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) may be used.

Administration of any chimeric protein (and/or additional agents) described herein can, independently, be one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years. Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject.

The dosage regimen utilizing any chimeric protein (and/or additional agents) described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific compound of the invention employed. Any chimeric protein (and/or additional agents) described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, any chimeric protein (and/or additional agents) described herein can be administered continuously rather than intermittently throughout the dosage regimen.

Cells and Nucleic Acids

In various embodiments, the present invention provides an expression vector, comprising a nucleic acid encoding the chimeric protein described herein. In various embodiments, the expression vector comprises DNA or RNA. In various embodiments, the expression vector is a mammalian expression vector.

Both prokaryotic and eukaryotic vectors can be used for expression of the chimeric protein. Prokaryotic vectors include constructs based on E. coli sequences (see, e.g., Makrides, Microbiol Rev 1996, 60:512-538). Non-limiting examples of regulatory regions that can be used for expression in E. coli include lac, trp, Ipp, phoA, recA, tac, T3, T7 and λP_(L). Non-limiting examples of prokaryotic expression vectors may include the λgt vector series such as λgt11 (Huynh et al., in “DNA Cloning Techniques, Vol. I: A Practical Approach,” 1984, (D. Glover, ed.), pp. 49-78, IRL Press, Oxford), and the pET vector series (Studier et al., Methods Enzymol 1990, 185:60-89). Prokaryotic host-vector systems cannot perform much of the post-translational processing of mammalian cells, however. Thus, eukaryotic host-vector systems may be particularly useful. A variety of regulatory regions can be used for expression of the chimeric proteins in mammalian host cells. For example, the SV40 early and late promoters, the cytomegalovirus (CMV) immediate early promoter, and the Rous sarcoma virus long terminal repeat (RSV-LTR) promoter can be used. Inducible promoters that may be useful in mammalian cells include, without limitation, promoters associated with the metallothionein II gene, mouse mammary tumor virus glucocorticoid responsive long terminal repeats (MMTV-LTR), the β-interferon gene, and the hsp70 gene (see, Williams et al., Cancer Res 1989, 49:2735-42; and Taylor et al., Mol Cell Biol 1990, 10:165-75). Heat shock promoters or stress promoters also may be advantageous for driving expression of the fusion proteins in recombinant host cells.

In some embodiments, expression vectors of the invention comprise a nucleic acid encoding the chimeric proteins (and/or additional agents), or a complement thereof, operably linked to an expression control region, or complement thereof, that is functional in a mammalian cell. The expression control region is capable of driving expression of the operably linked blocking and/or stimulating agent encoding nucleic acid such that the blocking and/or stimulating agent is produced in a human cell transformed with the expression vector.

Expression control regions are regulatory polynucleotides (sometimes referred to herein as elements), such as promoters and enhancers, that influence expression of an operably linked nucleic acid. An expression control region of an expression vector of the invention is capable of expressing operably linked encoding nucleic acid in a human cell. In an embodiment, the cell is a tumor cell. In another embodiment, the cell is a non-tumor cell. In an embodiment, the expression control region confers regulatable expression to an operably linked nucleic acid. A signal (sometimes referred to as a stimulus) can increase or decrease expression of a nucleic acid operably linked to such an expression control region. Such expression control regions that increase expression in response to a signal are often referred to as inducible. Such expression control regions that decrease expression in response to a signal are often referred to as repressible. Typically, the amount of increase or decrease conferred by such elements is proportional to the amount of signal present; the greater the amount of signal, the greater the increase or decrease in expression.

In an embodiment, the present invention contemplates the use of inducible promoters capable of effecting high level of expression transiently in response to a cue. For example, when in the proximity of a tumor cell, a cell transformed with an expression vector for the chimeric protein (and/or additional agents) comprising such an expression control sequence is induced to transiently produce a high level of the agent by exposing the transformed cell to an appropriate cue. Illustrative inducible expression control regions include those comprising an inducible promoter that is stimulated with a cue such as a small molecule chemical compound. Particular examples can be found, for example, in U.S. Pat. Nos. 5,989,910, 5,935,934, 6,015,709, and 6,004,941, each of which is incorporated herein by reference in its entirety.

Expression control regions and locus control regions include full-length promoter sequences, such as native promoter and enhancer elements, as well as subsequences or polynucleotide variants which retain all or part of full-length or non-variant function. As used herein, the term “functional” and grammatical variants thereof, when used in reference to a nucleic acid sequence, subsequence or fragment, means that the sequence has one or more functions of native nucleic acid sequence (e.g., non-variant or unmodified sequence).

As used herein, “operable linkage” refers to a physical juxtaposition of the components so described as to permit them to function in their intended manner. In the example of an expression control element in operable linkage with a nucleic acid, the relationship is such that the control element modulates expression of the nucleic acid. Typically, an expression control region that modulates transcription is juxtaposed near the 5′ end of the transcribed nucleic acid (i.e., “upstream”). Expression control regions can also be located at the 3′ end of the transcribed sequence (i.e., “downstream”) or within the transcript (e.g., in an intron). Expression control elements can be located at a distance away from the transcribed sequence (e.g., 100 to 500, 500 to 1000, 2000 to 5000, or more nucleotides from the nucleic acid). A specific example of an expression control element is a promoter, which is usually located 5′ of the transcribed sequence. Another example of an expression control element is an enhancer, which can be located 5′ or 3′ of the transcribed sequence, or within the transcribed sequence.

Expression systems functional in human cells are well known in the art, and include viral systems. Generally, a promoter functional in a human cell is any DNA sequence capable of binding mammalian RNA polymerase and initiating the downstream (3′) transcription of a coding sequence into mRNA. A promoter will have a transcription initiating region, which is usually placed proximal to the 5′ end of the coding sequence, and typically a TATA box located 25-30 base pairs upstream of the transcription initiation site. The TATA box is thought to direct RNA polymerase II to begin RNA synthesis at the correct site. A promoter will also typically contain an upstream promoter element (enhancer element), typically located within 100 to 200 base pairs upstream of the TATA box. An upstream promoter element determines the rate at which transcription is initiated and can act in either orientation. Of particular use as promoters are the promoters from mammalian viral genes, since the viral genes are often highly expressed and have a broad host range. Examples include the SV40 early promoter, mouse mammary tumor virus LTR promoter, adenovirus major late promoter, herpes simplex virus promoter, and the CMV promoter.

Typically, transcription termination and polyadenylation sequences recognized by mammalian cells are regulatory regions located 3′ to the translation stop codon and thus, together with the promoter elements, flank the coding sequence. The 3′ terminus of the mature mRNA is formed by site-specific post-translational cleavage and polyadenylation. Examples of transcription terminator and polyadenylation signals include those derived from SV40. Introns may also be included in expression constructs.

There are a variety of techniques available for introducing nucleic acids into viable cells. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, polymer-based systems, DEAE-dextran, viral transduction, the calcium phosphate precipitation method, etc. For in vivo gene transfer, a number of techniques and reagents may also be used, including liposomes; natural polymer-based delivery vehicles, such as chitosan and gelatin; viral vectors are also suitable for in vivo transduction. In some situations it is desirable to provide a targeting agent, such as an antibody or ligand specific for a tumor cell surface membrane protein. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g., capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sci. USA 87, 3410-3414 (1990).

Where appropriate, gene delivery agents such as, e.g., integration sequences can also be employed. Numerous integration sequences are known in the art (see, e.g., Nunes-Duby et al., Nucleic Acids Res. 26:391-406, 1998; Sadwoski, J. Bacteriol., 165:341-357, 1986; Bestor, Cell, 122(3):322-325, 2005; Plasterk et al., TIG 15:326-332, 1999; Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). These include recombinases and transposases. Examples include Cre (Sternberg and Hamilton, J. Mol. Biol., 150:467-486, 1981), lambda (Nash, Nature, 247, 543-545, 1974), Flp (Broach, et al., Cell, 29:227-234, 1982), R (Matsuzaki, et al., J. Bacteriology, 172:610-618, 1990), cpC31 (see, e.g., Groth et al., J. Mol. Biol. 335:667-678, 2004), sleeping beauty, transposases of the mariner family (Plasterk et al., supra), and components for integrating viruses such as AAV, retroviruses, and antiviruses having components that provide for virus integration such as the LTR sequences of retroviruses or lentivirus and the ITR sequences of AAV (Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). In addition, direct and targeted genetic integration strategies may be used to insert nucleic acid sequences encoding the chimeric fusion proteins including CRISPR/CAS9, zinc finger, TALEN, and meganuclease gene-editing technologies.

In one aspect, the invention provides expression vectors for the expression of the chimeric proteins (and/or additional agents) that are viral vectors. Many viral vectors useful for gene therapy are known (see, e.g., Lundstrom, Trends Biotechnol., 21: 1 17, 122, 2003. Illustrative viral vectors include those selected from Antiviruses (LV), retroviruses (RV), adenoviruses (AV), adeno-associated viruses (AAV), and α viruses, though other viral vectors may also be used. For in vivo uses, viral vectors that do not integrate into the host genome are suitable for use, such as α viruses and adenoviruses. Illustrative types of α viruses include Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV). For in vitro uses, viral vectors that integrate into the host genome are suitable, such as retroviruses, AAV, and Antiviruses. In one embodiment, the invention provides methods of transducing a human cell in vivo, comprising contacting a solid tumor in vivo with a viral vector of the invention.

In various embodiments, the present invention provides a host cell, comprising the expression vector comprising the chimeric protein described herein.

Expression vectors can be introduced into host cells for producing the present chimeric proteins. Cells may be cultured in vitro or genetically engineered, for example. Useful mammalian host cells include, without limitation, cells derived from humans, monkeys, and rodents (see, for example, Kriegler in “Gene Transfer and Expression: A Laboratory Manual,” 1990, New York, Freeman & Co.). These include monkey kidney cell lines transformed by SV40 (e.g., COS-7, ATCC CRL 1651); human embryonic kidney lines (e.g., 293, 293-EBNA, or 293 cells subcloned for growth in suspension culture, Graham et al., J Gen Virol 1977, 36:59); baby hamster kidney cells (e.g., BHK, ATCC CCL 10); Chinese hamster ovary-cells-DHFR (e.g., CHO, Urlaub and Chasin, Proc Natl Acad Sci USA 1980, 77:4216); DG44 CHO cells, CHO-K1 cells, mouse sertoli cells (Mather, Biol Reprod 1980, 23:243-251); mouse fibroblast cells (e.g., NIH-3T3), monkey kidney cells (e.g., CV1 ATCC CCL 70); African green monkey kidney cells. (e.g., VERO-76, ATCC CRL-1587); human cervical carcinoma cells (e.g., HELA, ATCC CCL 2); canine kidney cells (e.g., MDCK, ATCC CCL 34); buffalo rat liver cells (e.g., BRL 3A, ATCC CRL 1442); human lung cells (e.g., W138, ATCC CCL 75); human liver cells (e.g., Hep G2, HB 8065); and mouse mammary tumor cells (e.g., MMT 060562, ATCC CCL51). Illustrative cancer cell types for expressing the fusion proteins described herein include mouse fibroblast cell line, NIH3T3, mouse Lewis lung carcinoma cell line, LLC, mouse mastocytoma cell line, P815, mouse lymphoma cell line, EL4 and its ovalbumin transfectant, E.G7, mouse melanoma cell line, B16F10, mouse fibrosarcoma cell line, MC57, and human small cell lung carcinoma cell lines, SCLC#2 and SCLC#7.

Host cells can be obtained from normal or affected subjects, including healthy humans, cancer patients, and patients with an infectious disease, private laboratory deposits, public culture collections such as the American Type Culture Collection, or from commercial suppliers.

Cells that can be used for production of the present chimeric proteins in vitro, ex vivo, and/or in vivo include, without limitation, epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells (e.g., as obtained from bone marrow), umbilical cord blood, peripheral blood, fetal liver, etc. The choice of cell type depends on the type of tumor or infectious disease being treated or prevented, and can be determined by one of skill in the art.

Subjects and/or Animals

In some embodiments, the subject and/or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In other embodiments, the subject and/or animal is a non-mammal, such, for example, a zebrafish. In some embodiments, the subject and/or animal may comprise fluorescently-tagged cells (with e.g. GFP). In some embodiments, the subject and/or animal is a transgenic animal comprising a fluorescent cell.

In some embodiments, the subject and/or animal is a human. In some embodiments, the human is a pediatric human. In other embodiments, the human is an adult human. In other embodiments, the human is a geriatric human. In other embodiments, the human may be referred to as a patient.

In certain embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old.

In other embodiments, the subject is a non-human animal, and therefore the invention pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal.

Kits

The invention provides kits that can simplify the administration of any agent described herein. An illustrative kit of the invention comprises any composition described herein in unit dosage form. In one embodiment, the unit dosage form is a container, such as a pre-filled syringe, which can be sterile, containing any agent described herein and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. The kit can further comprise a label or printed instructions instructing the use of any agent described herein. The kit may also include a lid speculum, topical anesthetic, and a cleaning agent for the administration location. The kit can also further comprise one or more additional agent described herein. In one embodiment, the kit comprises a container containing an effective amount of a composition of the invention and an effective amount of another composition, such those described herein. The invention will be further described in the following example, which does not limit the scope of the invention described in the claims.

EXAMPLES Example 1. Construction and Characterization of Mouse PD-1-Fc-OX40L Construct

A chimeric mouse PD-1-Fc-OX40L construct was generated and its expression in CHO-K1 cells was verified using a mouse IgG capture ELISA assay (here, the Fc is derived from IgG1). Specifically, CHO-K1 cells were stably nucleofected with pVITRO2-GS-hygro or pcDNA3.4 vectors expressing either the mouse extracellular domain (ECD) of PD-1 fused to Fc (mPD-1-Fc) or mPD-1-Fc fused to the ECD of OX40L (mPD-1-Fc-OX40L). Antibiotic-resistant single cell clones were isolated via limiting dilution. The concentration of each chimeric protein secreted into the culture media was determined by a mIgG capture ELISA as shown in FIG. 5.

Binding assays were carried out to characterize the ability of mouse PD-1-Fc-OX40L to bind to mOX40 as well as to mPD-L1. FIG. 6, panel A, shows a schematic representation of the ELISA assay used to detect binding of mouse PD-1-Fc-OX40L to mOX40. Specifically, recombinant mOX40 fused to human Fc (mOX40-hFc) was used to capture mPD-1-Fc-OX40L in the culture media. A rabbit polyclonal antibody to mPD-1 was used to detect the mPD-1 domain in the chimeric protein and subsequently detected using a horseradish peroxidase (HRP)-conjugated polyclonal antibody to rabbit IgG (H+L). FIG. 6, panel B, shows that mouse PD-1-Fc-OX40L efficiently bound to OX40 compared to the mPD-1-Fc negative control. FIG. 7, panel A, shows a schematic representation of the ELISA assay used to detect binding of mouse PD-1-Fc-OX40L to mPD-L1. Specifically, recombinant mPD-L1 fused to human Fc (mPD-L1-hFc) was used to capture the mPD-1-Fc-OX40L chimeric protein in the culture media. A horseradish peroxidase (HRP)-conjugated polyclonal antibody to mouse IgG (H+L) was used for the detection of the bound proteins. FIG. 7, panel B, shows that mouse PD-1-Fc-OX40L efficiently bound to PD-L1 as compared to a negative media control and a positive control using recombinant mouse PD1-Fc.

Experiments were carried out to characterize the activity of mouse PD-1-Fc-OX40L in eliciting T-cell response and in treating tumors. Chicken ovalbumin antigen-specific OT-I/EGFP, CD8+ T cells (5×10⁵) were adoptively transferred to C57/BL6-albino mice via tail vein injections 2 days prior to inoculation with B16.F10-ova tumor cells (5×10⁵) into the right flank of the mice. Once tumors reached 3-5 mm in diameter, PD-1-Fc-OX40L expressing DNA (50 μg) was electroporated into the tumor using a defined electrical pulse (1500 V/cm) using 8 pulses at 100 μS. The percentage of CD8+ OT-I/EGFP cells in the peripheral blood was quantified by flow cytometry analysis over the assigned time course following electroporation. As shown in FIG. 8, in vivo intratumoral delivery of mouse (m) PD-1-Fc-OX40L led to an expansion of antigen-specific CD8+ T-cells.

FIG. 9 shows that the in vivo intratumoral delivery of mPD-1-Fc-OX40L also led to tumor regression in the B16.F10-ova tumor model. B16.F10-ova tumors were generated in C57/Bl6-albino mice that were adoptively transferred with CD8+ OT-I/EGFP cells and electroporated once with mPD-1-Fc-OX40L expressing DNA (50 μg). Control mice did not receive DNA but were subjected to electroporation (EP only). Tumor diameters were measured using a digital caliper over the assigned time course following electroporation. FIG. 9 demonstrates that the administration of mPD-1-Fc-OX40L significantly reduced tumor size.

Example 2. Additional Characterization of Mouse PD-1-Fc-OX40L Construct

A mPD-1-Fc-OX40L construct was generated which included the mouse extracellular domain (ECD) of PD-1 fused to the ECD of OX40L via a hinge-CH2-CH3 Fc domain derived from IgG1 (mPD-1-Fc-OX40L). The mPD-1-Fc-OX40L construct was transiently expressed in 293 cells and purified using protein A affinity chromatography. Western blot and functional ELISA analysis were performed to validate the detection and binding of all 3 components of mPD-1-Fc-OX40L (FIG. 10, panel A). Quanitation of mPD1-Fc-OX40L can be assessed using a murine IgG capture and detection ELISA (FIG. 10, panel B). The binding of mPD-1 and mOX40L to their partners mPD-L1 and mOX40, respectively, was demonstrated simultaneously by capturing mPD-1-Fc-OX40L with mPD-L1-Fc and detecting it with mOX40-His, followed by His-HRP for chemiluminescence quantitation (FIG. 8, panel C). It was also noted that there were monomeric and dimeric conformations of mPD-1-Fc-OX40L.

To assess the ex vivo cellular binding of mPD-1-Fc-OX40L, primary mouse splenocytes were isolated and activated for 2 days with PMA/PHA/Ionomycin, in order to up-regulate OX40 and PD-L1 expression. Activated splenocytes were then treated with 500 ng/mL of mPD-1-Fc-OX40L and analyzed by flow cytometry for binding (Fc-PE) (FIG. 8, panel D). To isolate PD-L1 expressing cells, splenocytes were co-stained with an antibody targeting MHC II on antigen presenting cells (I-A/I-E). To isolate OX40 expressing cells, splenocytes were co-stained with CD4. mPD-1-Fc-OX40L bound significantly to both PD-L1+ and OX40+ populations of splenocytes, indicating that mPD-1-Fc-OX40L had been generated and purified competently to bind its targets on primary derived cells. The binding activity of mPD1-Fc-OX40L to primary mouse tumor cell lines expressing PD-L1 was also assessed. The murine 4T1 tumor cell line was identified as expressing low amounts of PD-L1 and the B16.F10 tumor cell line expressed comparatively high amounts of PD-L1. mPD1-Fc-OX40L was shown to bind the PD-L1 positive B16.F10 tumor cell line to a greater extent than the PD-L1 low 4T1 tumor cell line (FIG. 10, panel E).

Additional functional activities of mPD-1-Fc-OX40L were characterized using a T cell activation/tumor co-culture assay. First, murine (4T1) and PD-L1_(high) (B16.F10) cells were identified by flow cytometry (FIG. 8, panel E). Next, mouse splenocytes were activated for 2 days with CD3/CD28 beads and a sub-saturating concentration of IL2. After 2 days, activated splenocytes were co-cultured with either irradiated 4T1 or B16.F10 cells in the presence or absence of mPD-1-Fc-OX40L. Five days after the initial isolation of splenocytes, culture medium was collected and analyzed for the cytokine IL2 by ELISA (FIG. 8, panel F). It was observed that mPD-1-Fc-OX40L was capable of significant induction of IL2 secretion, especially in co-cultures containing PD-L1_(high) tumor cells. Without wishing to be bound by theory, it is believed that mPD-1-Fc-OX40L was concomitantly blocking the suppressive effects of PD-L1 while also activating T cells via OX40/OX40L signaling, thereby inducing IL2 secretion. Altogether, these findings suggest that mPD-1-Fc-OX40L may provide significant anti-tumor immunity in pre-clinical models.

The anti-tumor potency of mPD-1-Fc-OX40L was tested using several preclinical tumor model systems. Specifically murine models of colorectal cancer (CT26 and MC38) were used to assess the effects of mPD-1-Fc-OX40L on tumor growth, overall survival, and the induction of a serum cytokine response following therapy. These experiments were performed head-to-head with extensively characterized OX40 agonist (OX86) and PD-L1 blocking (10F.9G2) antibodies given as monotherapy or in combination, at an equivalent active dose to mPD-1-Fc-OX40L via intraperitoneal injection (2 doses of 100 ug each). As shown in FIG. 11, panel A, mPD-1-Fc-OX40L significantly reduced tumor size in the MC38 model. More particularly, administration of mPD-1-Fc-OX40L resulted in greater tumor regression than the OX40 agonist and PD-L1 blocking antibodies administered individually or in combination. Importantly, repeat challenge of mice that rejected the primary tumor with the parental MC38 tumor cell line was performed for each group. These data demonstrated that, in the absence of repeat treatment, mice treated with mPD1-Fc-OX40L were able to reject a re-challenge with the parental tumor to a greater degree than any of the other treatment groups (FIG. 11, panels A and B). Further, other fusion constructs including mPD1-Fc-GITRL and mPD1-Fc-41BBL were produced and used in tumor bearing mice as described above for mPD1-Fc-OX40L. Both the GITRL and 41BBL containing constructs led to reduced tumor size in treated animals.

In addition to measuring tumor size, a pharmacodynamic biomarker for mPD-1-Fc-OX40L signaling in vivo was also determined. Specifically, a serum cytokine analysis for mice treated with anti-PD-L1 and anti-OX40 antibodies as well as with PD-1-Fc-OX40L was performed. As shown in FIG. 11, panels B and C, there was a dose-dependent cytokine signature following treatment with mPD-1-Fc-OX40L that was remarkably similar to the cytokine signature observed following combined administration of anti-PD-L1 and anti-OX40 antibodies, comprising of increased IFNγ, TNFα, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A and IL-22 (FIG. 11, panels C, D & J). Importantly, detection of a serum cytokine response following treatment with mPD1-Fc-OX40L was shown to be dose dependent. Specifically, treatment with one or two injections of 40 μg did not lead to a detectable serum cytokine response, while treatment with 100 μg once led to an intermediate cytokine response and treatment with 100 μg two times led to a higher cytokine response (FIG. 11, panel K). Treatment of mice with mPD1-Fc-GITRL was also shown to stimulated a specific serum cytokine response.

In some experiments, mice bearing MC38 tumors were sacrificed on day 13 of the experiment to evaluate the cellular immune response in the tumor, peripheral blood and spleen. On day 13 of the experiment, mPD1-Fc-OX40L, mPD1-Fc-GITRL and mCD172a-Fc-CD40L were all shown to cause reduced tumor growth as compared to untreated animals or animals treated with OX40 agonist antibodies, GITR agonist antibodies or PD-L1 blocking antibodies (FIG. 11, panel E). In accordance with these data, mice treated with mPD1-Fc-OX40L or mPD1-Fc-GITRL were shown to have increased numbers of tumor antigen specific tumor infiltrating lymphocytes (TIL) on day 13 of the experiment (FIG. 11, panel F). Analysis of the memory phenotype in the spleen of CD8+ T cells was performed (FIG. 11, panel G) and the CD4/CD8 T cell ratio was also compared across multiple treatments (FIG. 11, panel H).

The pharmacodynamic biomarkers for PD-1-Fc-OX40L signaling in vivo was also determined using the CT26 model. Specifically, a serum cytokine analysis for mice treated with anti-PD-L1 and anti-OX40 antibodies, individually or in combination, as well as with PD-1-Fc-OX40L was performed. As shown in FIG. 11, panel D, the cytokine signature following treatment with mPD-1-Fc-OX40L was remarkably similar to the cytokine signature observed following the combined administration of anti-PD-L1 and anti-OX40 antibodies. Specifically, the cytokine signature comprised of increased IFNγ, TNFα, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, and IL-22 (FIG. 11, panels J and K).

Consistent with the results derived from the MC38 model, administration of mPD-1-Fc-OX40L also significantly reduced tumor size in the CT26 colorectal cancer model. Particularly, use of mPD-1-Fc-OX40L resulted in greater tumor regression than the OX40 agonist and PD-L1 blocking antibodies (FIG. 11, panel L). Further, mice administered with mPD-1-Fc-OX40L exhibited longer survival time than mice administered with the OX40 agonist and PD-L1 blocking antibodies (FIG. 11, panel L). In addition, other chimeric fusion protein constructs including PD1-Fc-GITRL, PD1-Fc-41BBL and PD1-Fc-TL1A were all shown to exhibit delayed tumor growth an regression in the CT26 model (FIG. 11, panel L).

Altogether, these data clearly demonstrate, inter alia, the functional activity of mPD-1-Fc-OX40L in vivo.

Example 3. Construction and Characterization of Human PD-1-Fc-OX40L

A human PD-1-Fc-OX40L comprising human PD-1 linked to OX40L via a hinge-CH2-CH3 Fc domain derived from the human immunoglobulin 4 (IgG4) antibody was constructed. This construct was referred to as SL-279252.

The mRNA sequence of human OX40L was as follows (bold text—CDS of OX40L; bold & underlined text—extracellular domain of OX40L):

(SEQ ID NO: 16)    1 TCAATCGCCTTTTATCTCTGGCCCTGGGACCTTTGCCTATTTTCTGATTGATAGGCTTTG   61 TTTTGTCTTTACCTCCTTCTTTCTGGGGAAAACTTCAGTTTTATCGCACGTTCCCCTTTT  121 CCATATCTTCATCTTCCCTCTACCCAGATTGTGAAGATGGAAAGGGTCCAACCCCTGGAA  181 GAGAATGTGGGAAATGCAGCCAGGCCAAGATTCGAGAGGAACAAGCTATTGCTGGTGGCC  241 TCTGTAATTCAGGGACTGGGGCTGCTCCTGTGCTTCACCTACATCTGCCTGCACTTCTCT  301 GCTCTT CAGGTATCACATCGGTATCCTCGAATTCAAAGTATCAAAGTACAATTTACCGAA  361 TATAAGAAGGAGAAAGGTTTCATCCTCACTTCCCAAAAGGAGGATGAAATCATGAAGGTG  421 CAGAACAACTCAGTCATCATCAACTGTGATGGGTTTTATCTCATCTCCCTGAAGGGCTAC  481 TTCTCCCAGGAAGTCAACATTAGCCTTCATTACCAGAAGGATGAGGAGCCCCTCTTCCAA  541 CTGAAGAAGGTCAGGTCTGTCAACTCCTTGATGGTGGCCTCTCTGACTTACAAAGACAAA  601 GTCTACTTGAATGTGACCACTGACAATACCTCCCTGGATGACTTCCATGTGAATGGCGGA  661 GAACTGATTCTTATCCATCAAAATCCTGGTGAATTCTGTGTCCTTTGA GGGGCTGATGGC  721 AATATCTAAAACCAGGCACCAGCATGAACACCAAGCTGGGGGTGGACAGGGCATGGATTC  781 TTCATTGCAAGTGAAGGAGCCTCCCAGCTCAGCCACGTGGGATGTGACAAGAAGCAGATC  841 CTGGCCCTCCCGCCCCCACCCCTCAGGGATATTTAAAACTTATTTTATATACCAGTTAAT  901 CTTATTTATCCTTATATTTTCTAAATTGCCTAGCCGTCACACCCCAAGATTGCCTTGAGC  961 CTACTAGGCACCTTTGTGAGAAAGAAAAAATAGATGCCTCTTCTTCAAGATGCATTGTTT 1021 CTATTGGTCAGGCAATTGTCATAATAAACTTATGTCATTGAAAACGGTACCTGACTACCA 1081 TTTGCTGGAAATTTGACATGTGTGTGGCATTATCAAAATGAAGAGGAGCAAGGAGTGAAG 1141 GAGTGGGGTTATGAATCTGCCAAAGGTGGTATGAACCAACCCCTGGAAGCCAAAGCGGCC 1201 TCTCCAAGGTTAAATTGATTGCAGTTTGCATATTGCCTAAATTTAAACTTTCTCATTTGG 1261 TGGGGGTTCAAAAGAAGAATCAGCTTGTGAAAAATCAGGACTTGAAGAGAGCCGTCTAAG 1321 AAATACCACGTGCTTTTTTTCTTTACCATTTTGCTTTCCCAGCCTCCAAACATAGTTAAT 1381 AGAAATTTCCCTTCAAAGAACTGTCTGGGGATGTGATGCTTTGAAAAATCTAATCAGTGA 1441 CTTAAGAGAGATTTTCTTGTATACAGGGAGAGTGAGATAACTTATTGTGAAGGGTTAGCT 1501 TTACTGTACAGGATAGCAGGGAACTGGACATCTCAGGGTAAAAGTCAGTACGGATTTTAA 1561 TAGCCTGGGGAGGAAAACACATTCTTTGCCACAGACAGGCAAAGCAACACATGCTCATCC 1621 TCCTGCCTATGCTGAGATACGCACTCAGCTCCATGTCTTGTACACACAGAAACATTGCTG 1681 GTTTCAAGAAATGAGGTGATCCTATTATCAAATTCAATCTGATGTCAAATAGCACTAAGA 1741 AGTTATTGTGCCTTATGAAAAATAATGATCTCTGTCTAGAAATACCATAGACCATATATA 1801 GTCTCACATTGATAATTGAAACTAGAAGGGTCTATAATCAGCCTATGCCAGGGCTTCAAT 1861 GGAATAGTATCCCCTTATGTTTAGTTGAAATGTCCCCTTAACTTGATATAATGTGTTATG 1921 CTTATGGCGCTGTGGACAATCTGATTTTTCATGTCAACTTTCCAGATGATTTGTAACTTC 1981 TCTGTGCCAAACCTTTTATAAACATAAATTTTTGAGATATGTATTTTAAAATTGTAGCAC 2041 ATGTTTCCCTGACATTTTCAATAGAGGATACAACATCACAGAATCTTTCTGGATGATTCT 2101 GTGTTATCAAGGAATTGTACTGTGCTACAATTATCTCTAGAATCTCCAGAAAGGTGGAGG 2161 GCTGTTCGCCCTTACACTAAATGGTCTCAGTTGGATTTTTTTTTCCTGTTTTCTATTTCC 2221 TCTTAAGTACACCTTCAACTATATTCCCATCCCTCTATTTTAATCTGTTATGAAGGAAGG 2281 TAAATAAAAATGCTAAATAGAAGAAATTGTAGGTAAGGTAAGAGGAATCAAGTTCTGAGT 2341 GGCTGCCAAGGCACTCACAGAATCATAATCATGGCTAAATATTTATGGAGGGCCTACTGT 2401 GGACCAGGCACTGGGCTAAATACTTACATTTACAAGAATCATTCTGAGACAGATATTCAA 2461 TGATATCTGGCTTCACTACTCAGAAGATTGTGTGTGTGTTTGTGTGTGTGTGTGTGTGTG 2521 TATTTCACTTTTTGTTATTGACCATGTTCTGCAAAATTGCAGTTACTCAGTGAGTGATAT 2581 CCGAAAAAGTAAACGTTTATGACTATAGGTAATATTTAAGAAAATGCATGGTTCATTTTT 2641 AAGTTTGGAATTTTTATCTATATTTCTCACAGATGTGCAGTGCACATGCAGGCCTAAGTA 2701 TATGTTGTGTGTGTTGTTTGTCTTTGATGTCATGGTCCCCTCTCTTAGGTGCTCACTCGC 2761 TTTGGGTGCACCTGGCCTGCTCTTCCCATGTTGGCCTCTGCAACCACACAGGGATATTTC 2821 TGCTATGCACCAGCCTCACTCCACCTTCCTTCCATCAAAAATATGTGTGTGTGTCTCAGT 2881 CCCTGTAAGTCATGTCCTTCACAGGGAGAATTAACCCTTCGATATACATGGCAGAGTTTT 2941 GTGGGAAAAGAATTGAATGAAAAGTCAGGAGATCAGAATTTTAAATTTGACTTAGCCACT 3001 AACTAGCCATGTAACCTTGGGAAAGTCATTTCCCATTTCTGGGTCTTGCTTTTCTTTCTG 3061 TTAAATGAGAGGAATGTTAAATATCTAACAGTTTAGAATCTTATGCTTACAGTGTTATCT 3121 GTGAATGCACATATTAAATGTCTATGTTCTTGTTGCTATGAGTCAAGGAGTGTAACCTTC 3181 TCCTTTACTATGTTGAATGTATTTTTTTCTGGACAAGCTTACATCTTCCTCAGCCATCTT 3241 TGTGAGTCCTTCAAGAGCAGTTATCAATTGTTAGTTAGATATTTTCTATTTAGAGAATGC 3301 TTAAGGGATTCCAATCCCGATCCAAATCATAATTTGTTCTTAAGTATACTGGGCAGGTCC 3361 CCTATTTTAAGTCATAATTTTGTATTTAGTGCTTTCCTGGCTCTCAGAGAGTATTAATAT 3421 TGATATTAATAATATAGTTAATAGTAATATTGCTATTTACATGGAAACAAATAAAAGATC 3481 TCAGAATTCACTA

The amino acid sequence of human OX40L was as follows (bolded—extracellular domain):

(SEQ ID NO: 17) MERVQPLEENVGNAARPRFERNKLLLVASVIQGLGLLLCFTYICLHFSAL QVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGF YLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVY LNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL

The nucleic acid sequence of the hinge-CH2-CH3 Sequence from human IgG4 was as follows:

(SEQ ID NO: 18) TCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCCCTGAATTTCTGGG CGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGA TCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGATGTGTCCCAGGAA GATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGGTGGAAGTGCACAA CGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGCACCTACCGGGTGG TGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAGCGGCAAAGAGTAC AAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCATCGAAAAGACCAT CAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTGTACACACTGCCCC CTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCTGACATGCCTCGTG AAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAACGGCCA GCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCT CATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAGCAGCTGGCAGGAA GGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAACCACTA CACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAA 

The cDNA sequence of human PD-1 was as follows:

(SEQ ID NO: 19) ATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCTACAACT GGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAGGCCCTGGAACC CCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGACCGAAGGGGACAACGCC ACCTTCACCTGCAGCTTCTCCAACACATCGGAGAGCTTCGTGCTAAACTG GTACCGCATGAGCCCCAGCAACCAGACGGACAAGCTGGCCGCCTTCCCCG AGGACCGCAGCCAGCCCGGCCAGGACTGCCGCTTCCGTGTCACACAACTG CCCAACGGGCGTGACTTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGA CAGCGGCACCTACCTCTGTGGGGCCATCTCCCTGGCCCCCAAGGCGCAGA TCAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAGAGAAGGGCAGAA GTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGCCGGCCAGTTCCA AACCCTGGTGGTTGGTGTCGTGGGCGGCCTGCTGGGCAGCCTGGTGCTGC TAGTCTGGGTCCTGGCCGTCATCTGCTCCCGGGCCGCACGAGGGACAATA GGAGCCAGGCGCACCGGCCAGCCCCTGAAGGAGGACCCCTCAGCCGTGCC TGTGTTCTCTGTGGACTATGGGGAGCTGGATTTCCAGTGGCGAGAGAAGA CCCCGGAGCCCCCCGTGCCCTGTGTCCCTGAGCAGACGGAGTATGCCACC ATTGTCTTTCCTAGCGGAATGGGCACCTCATCCCCCGCCCGCAGGGGCTC AGCTGACGGCCCTCGGAGTGCCCAGCCACTGAGGCCTGAGGATGGACACT GCTCTTGGCCCCTCTGA 

The nucleic acid sequence of human PD-1-Fc-OX40L was as follows:

(SEQ ID NO: 20) GTCGACGCCACCATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGC GGTGCTACAACTGGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACA GGCCCTGGAACCCCCCCACCTTCTCCCCAGCCCTGCTCGTGGTGACCGAA GGGGACAACGCCACCTTCACCTGCAGCTTCTCCAACACATCGGAGAGCTT CGTGCTAAACTGGTACCGCATGAGCCCCAGCAACCAGACGGACAAGCTGG CCGCCTTCCCCGAGGACCGCAGCCAGCCCGGCCAGGACTGCCGCTTCCGT GTCACACAACTGCCCAACGGGCGTGACTTCCACATGAGCGTGGTCAGGGC CCGGCGCAATGACAGCGGCACCTACCTCTGTGGGGCCATCTCCCTGGCCC CCAAGGCGCAGATCAAAGAGAGCCTGCGGGCAGAGCTCAGGGTGACAGAG AGAAGGGCAGAAGTGCCCACAGCCCACCCCAGCCCCTCACCCAGGCCAGC CGGCCAGTTCCAATCTAAGTACGGCCCTCCCTGCCCTAGCTGTCCCGCCC CTGAATTTCTGGGCGGACCCTCCGTGTTTCTGTTCCCCCCAAAGCCCAAG GACACCCTGATGATCAGCCGGACCCCCGAAGTGACCTGTGTGGTGGTGGA TGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGTGGACGGGG TGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTTCAACAGC ACCTACCGGGTGGTGTCTGTGCTGACCGTGCTGCACCAGGATTGGCTGAG CGGCAAAGAGTACAAGTGCAAGGTGTCCAGCAAGGGCCTGCCCAGCAGCA TCGAAAAGACCATCAGCAACGCCACCGGCCAGCCCAGGGAACCCCAGGTG TACACACTGCCCCCTAGCCAGGAAGAGATGACCAAGAACCAGGTGTCCCT GACATGCCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGG AGAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTG GACAGCGACGGCTCATTCTTCCTGTACTCCCGGCTGACAGTGGACAAGAG CAGCTGGCAGGAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCC TGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCTGGGCAAAATA GAGGGACGAATGGACcaggtatcacatcggtatcctcgaattcaaagtat caaagtacaatttaccgaatataagaaggagaaaggtttcatcctcactt cccaaaaggaggatgaaatcatgaaggtgcagaacaactcagtcatcatc aactgtgatgggttttatctcatctccctgaagggctacttctcccagga agtcaacattagccttcattaccagaaggatgaggagcccctcttccaac tgaagaaggtcaggtctgtcaactccttgatggtggcctctctgacttac aaagacaaagtctacttgaatgtgaccactgacaatacctccctggatga cttccatgtgaatggcggagaactgattcttatccatcaaaatcctggtg aattctgtgtccttTGAGTCGAC 

The sequence was codon optimized for expression by Chinese Hamster (CHO) cells as follows:

(SEQ ID NO: 21) CACCGGCGAGATCTGCCACCATGCAGATCCCTCAGGCCCCCTGGCCTGTC GTGTGGGCTGTGCTGCAGCTGGGATGGCGGCCTGGCTGGTTCCTGGACTC TCCTGACAGACCCTGGAACCCCCCCACCTTTAGCCCTGCTCTGCTGGTCG TGACCGAGGGCGACAACGCCACCTTCACCTGTTCCTTCAGCAACACCTCC GAGTCCTTCGTGCTGAACTGGTACAGAATGTCCCCCAGCAACCAGACCGA CAAGCTGGCCGCCTTCCCCGAGGATAGATCCCAGCCTGGACAGGACTGCC GGTTCAGAGTGACCCAGCTGCCCAACGGCCGGGACTTCCACATGTCTGTC GTGCGGGCCAGACGGAACGACTCCGGCACATATCTGTGCGGCGCCATCTC CCTGGCCCCCAAGGCTCAGATCAAAGAGTCTCTGCGGGCCGAGCTGAGAG TGACCGAGAGAAGGGCTGAGGTGCCAACCGCCCACCCTAGCCCATCTCCA AGACCTGCCGGCCAGTTCCAGTCTAAGTACGGCCCTCCTTGCCCTAGCTG CCCTGCCCCTGAATTTCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCAA AGCCCAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTG GTGGTGGATGTGTCCCAGGAAGATCCCGAGGTGCAGTTCAATTGGTACGT GGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGT TCAACTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT TGGCTGTCCGGCAAAGAGTACAAGTGCAAGGTGTCCTCCAAGGGCCTGCC CTCCAGCATCGAAAAGACCATCTCTAACGCCACCGGCCAGCCCCGGGAAC CCCAGGTGTACACACTGCCTCCAAGCCAGGAAGAGATGACCAAGAACCAG GTGTCCCTGACCTGTCTCGTGAAGGGCTTCTACCCCTCCGATATCGCCGT GGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTACAAGACCACCCCCC CTGTGCTGGACTCCGACGGCTCCTTCTTCCTGTACTCCCGCCTGACCGTG GACAAGTCCTCCTGGCAGGAAGGCAACGTGTTCTCCTGCTCCGTGATGCA CGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGTCTCTGG GCAAGATCGAGGGCCGGATGGATCAGGTGTCACACAGATACCCCCGGATC CAGTCCATCAAAGTGCAGTTTACCGAGTACAAGAAAGAGAAGGGATTCAT CCTGACCTCCCAGAAAGAGGACGAGATCATGAAGGTGCAGAACAACTCCG TGATCATCAACTGCGACGGGTTCTACCTGATCTCCCTGAAGGGCTACTTC AGTCAGGAAGTGAACATCAGCCTGCACTACCAGAAGGACGAGGAACCCCT GTTCCAGCTGAAGAAAGTGCGGAGCGTGAACTCCCTGATGGTGGCCTCTC TGACCTACAAGGACAAGGTGTACCTGAACGTGACCACCGACAATACCTCC CTGGACGACTTCCACGTGAACGGCGGCGAGCTGATCCTGATCCACCAGAA CCCTGGCGAGTTCTGCGTGCTGTGACTCGAGGCTAGC 

Accordingly, the amino acid sequence of SL-279252 was as follows:

(SEQ ID NO: 22) MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNA TFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQL PNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAE VPTAHPSPSPRPAGQFQSKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRM DQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDG FYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKV YLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL 

Alternatively, SL-279252 may include other signaling peptides such as those derived from human collagen V or human IgG heavy chain. Alternatively, SL-279252 may include one or more mutations in the Fc domain to increase stability or to increase binding affinity to FcRn, such as those previously described. The human PD-1-Fc-OX40L construct was imported into the protein tertiary prediction software RaptorX, to ensure proper folding of the three major domains (see FIG. 12, panel A). The tertiary structures of each component (i.e., PD-1, Fc, and OX40L) adopted their native conformations within the larger macromolecule, suggesting that PD-1-Fc-OX40L would retain binding capability and molecular function of all domains. Next, the immunogenic probability of PD-1-Fc-OX40L was assessed using an in silico molecular modeling algorithm, cross-referenced to a T cell epitope database (ABZENA/ANTITOPE, FIG. 12, panel B). Although all coding sequences were human, there was minimal potential for lead and linker sequences to elicit an immune response following treatment. Further analysis was performed using the iTope antigen prediction technology in silico (ANTITOPE). Based on this analysis, SL-279252 was predicted to have a ‘low-risk’ of immunogenicity because no identifiable T cell epitopes were detected. Accordingly, SL-279252 was expected to have low immunogenicity.

The codon-optimized DNA sequence of SL-279252 was then synthesized and directionally cloned into pcDNA3.4-hygro-mcs (THERMO FISHER) and pVITRO2-hygro-mcs (INVIVOGEN) expression vectors. Vectors were then either transiently or stably transfected into CHO-K1 and 293T cells, and culture supernatants were purified using standard protein A agarose affinity chromatography. Human Fc/IgG ELISAs on eluted fractions (from stable transfection experiments) of purified protein show definitive peaks that align with the first major peak detected from a large-scale purification obtained from transient transfection experiments (FIG. 13, panel A), indicating that successful production of SL-279252 can be achieved using routine protein purification techniques such as protein A.

To confirm that all three domains of SL-279252 are intact and recognizable by a protein detection assay, Western blot analysis was performed on purified fusion protein probing for human anti-PD-1, anti-Fc, and anti-OX40L (FIG. 13, panel B). SL-279252 was detected by all three antibodies and when the protein was run under reducing conditions, migrated at approximately 75 kDa. Approximately 50% of the non-reduced protein ran as a dimer, which was a potential advantage, given the in vivo oligomerization associated with OX40/L signaling and function. The predicted molecular weight for SL-279252 was 60.3 kDa. The reduced fraction of SL-279252 was detected at a higher molecular weight, which, without wishing to be bound by theory, may be due to glycosylation. This was verified by treating SL-279252 with a protein deglycosylase, PNGase F (FIG. 13, panel B). Following deglycosylation, the reduced fraction of SL-279252 migrated exactly at the predicted molecular weight of 60.3 kDa. This provided evidence that SL-279252 was co/post-translationally modified through glycosylation, which played essential roles in the proper folding and stability of proteins, and cell-to-cell adhesion (Dalziel M, Dwek R A. Science 2014, Maverakis E, Lebrilla C B. J Autoimmun. 2015).

Next, analysis was performed to determine whether SL-279252 was able to bind to its receptor/ligand targets using plate-immobilized recombinant proteins in functional ELISA assays. SL-279252 was successfully captured with recombinant human OX40 (FIG. 13, panel C), and detected with anti-human OX40L/anti-goat HRP. In this regard, the capture of SL-279252 with human OX40, followed by detection with a two-step incubation with goat-anti-OX40L followed by anti-goat-HRP led to efficient detection. To establish whether both ends of SL-279252 could bind their respective receptor/ligand simultaneously, another ELISA assay was developed which captures SL-279252 using plate absorbed human PD-L1 and detects SL-279252 using recombinant OX40-his (FIG. 13, panel D). This assay demonstrates that SL-279252 can simultaneously bind human PD-L1 and human OX40.

Next, surface plasmon resonance (SPR) analysis was performed to determine the affinity by which SL-279252 bound to hPD-L1, hPD-L1, hOX40 and various human Fc receptors (FIG. 14). Specifically, polyhistidine-tagged versions of recombinant human PD-L1, PD-L2 and human OX40 was bound to ProteOn HTG tris-NTA chips (BIORAD). SL-279252 was then flowed over the bound ligands over a time course and a relative index of ‘on-rate’ (Ka) and ‘off-rate’ (Kd) was generated to calculate binding affinity (K_(D)) of SL-279252 to each partner. Recombinant human PD-1-Fc and OX40L-Fc were used as positive controls for binding. These controls have a relatively fast ‘on-rate’ and an equally fast ‘off-rate’, resulting in low nanomolar binding affinities. Consistent with these results, the ‘on-rate’ of SL-279252 to human PD-L1 was rapid, however the ‘off-rate’ was much lower, in fact ˜20-fold slower than the ‘off-rate’ of recombinant PD-1-Fc, indicating that SL-279252 bound quickly and stably, with long on-target residence time (FIG. 14, panel A). The K_(D) of SL-279252 binding to human PD-L1 was calculated to be 2.08 nM, nearly identical to the observed K_(D) of BMS's OPDIVO (˜4 nM). The K_(D) of SL-279252 binding to human PD-L2 was calculated to be 1.24 nM (FIG. 14, panel B). SL-279252 bound with high affinity to human OX40 (246 pM), again with a fast ‘on-rate’ and slow ‘off-rate’ (FIG. 14, panel C).

To further define the molecular characteristics of SL-279252, SPR was performed, analyzing the binding affinities of SL-279252 to chip-bound, Fcγ receptors FcγR1A and to the neonatal receptor, FcRn. The human immunoglobulin IgG1 was shown to bind with the highest affinities to FcγR1A, followed by FcRn, in addition to low-level binding to FcγR2b (FIG. 14, panel C and D). SL-279252 did not bind to FcγR1A or FcγR2B, but did bind to FcRn at 73 nM affinity (FIG. 14, panel D and E). Without wishing to be bound by theory, this binding characteristic may be important to the fusion protein because FcRn is involved in IgG recycling to the surface of a cell, thereby avoiding lysosomal degradation, and potentially extending the in vivo half-life of SL-279252. Summary data for SL-279252 binding affinities are including (FIG. 14, panel F).

Next, surface plasmon resonance (SPR) analysis was performed to determine the affinity by which a mutated SL-279252 construct containing a collagen V leader peptide and Fc region mutations to increase binding to FcRn (named colPD1-FcRnOX40L) was examined for binding to hPD-L1, hPD-L1, hOX40 and various human Fc receptors (FIG. 14). Specifically, polyhistidine-tagged versions of recombinant human PD-L1, PD-L2 and human OX40 was bound to ProteOn HTG tris-NTA chips (BIORAD). colPD1-FcRnOX40L was then flowed over the bound ligands over a time course and a relative index of ‘on-rate’ (Ka) and ‘off-rate’ (Kd) was generated to calculate binding affinity (K_(D)) of colPD1-FcRnOX40L to each partner. Recombinant human PD-1-Fc and OX40L-Fc were used as positive controls for binding. These controls have a relatively fast ‘on-rate’ and an equally fast ‘off-rate’, resulting in low nanomolar binding affinities. Consistent with these results, the ‘on-rate’ of colPD1-FcRnOX40L to human PD-L1 was rapid, however the ‘off-rate’ was much lower, in fact ˜10-fold slower than the ‘off-rate’ of recombinant PD-1-Fc, indicating that colPD1-FcRnOX40L bound quickly and stably, with long on-target residence time (FIG. 14, panel G). The K_(D) of colPD1-FcRnOX40L binding to human PD-L1 was calculated to be 6.35 nM, nearly identical to the observed K_(D) of BMS's OPDIVO (˜4 nM). The K_(D) of colPD1-FcRnOX40L binding to human PD-L2 was calculated to be 7.93 nM (FIG. 14, panel H). colPD1-FcRnOX40L bound with high affinity to human OX40 (9.61 nM), again with a fast ‘on-rate’ and slow ‘off-rate’ (FIG. 14, panel I).

To further define the molecular characteristics of colPD1-FcRnOX40L, SPR was performed, analyzing the binding affinities of colPD1-FcRnOX40L to chip-bound, Fcγ receptors FcγR1A and to the neonatal receptor, FcRn. The human immunoglobulin IgG1 was shown to bind with the highest affinities to FcγR1A, followed by FcRn, in addition to low-level binding to FcγR2b (FIG. 14, panel J and K). colPD1-FcRnOX40L did not bind to FcγR1A or FcγR2B, but did bind to FcRn at 2.51 nM affinity (FIG. 14, panel K). Without wishing to be bound by theory, this binding characteristic may be important to the fusion protein because FcRn is involved in IgG recycling to the surface of a cell, thereby avoiding lysosomal degradation, and potentially extending the in vivo half-life of colPD1-FcRnOX40L. Summary data for colPD1-FcRnOX40L binding affinities are including (FIG. 14, panel L).

Additionally, the in vivo half-life of the purified SL-279252 was tested in C57BL/6 mice by injecting 200 μg of the protein by intra-peritoneal injection. Blood was then collected from treated animals by cardiac puncture at 10 minutes, 30 minutes, 1 hour, 3, 6, 12 and 24 hours and allowed to clot for 2 hours at room temperature. The serum was then assayed using a human IgG or OX40L specific ELISA as outlined above. As shown in FIG. 14, panel M, the serum half-life of SL-279252 in mice following a single injection of 200 μg of protein was determined to be between 7-15 hours. It is anticipated that constructs containing mutations to increase binding affinity to FcRn will lead to longer half-life in vivo.

The slow off-rates detected by SPR suggested that SL-279252 may have a longer on-target (i.e. intratumoral) half-life than serum half life. To investigate this question, immunocompromised NSG mice were implanted with a PD-L1 negative HeLa (human cervical cancer) tumor on one flank, and with a PD-L1 expressing HeLa tumor on the opposite flank. Mice were treated with single injections of 200 μg of SL-279252 and individual mice were sacrificed at defined time points. At the time of sacrifice, both HeLa tumors were excised and bisected. Half of the tumor was dissociated and analyzed for SL-279252 binding by flow cytometry. This analysis demonstrated that SL-279252 accumulated specifically in PD-L1 positive, but not PD-L1 negative tumors. The concentration of SL-279252 was observed to increase in the tumor up to 48 hours post treatment (FIG. 14, panel N). Further, immunohistochemical analysis of the other half of each tumor demonstrated that significant staining for human OX40L was present 5 days post treatment, suggesting that SL-279252 was detectable in PD-L1 positive human tumors at least 5 days following a single treatment (FIG. 14, panel O).

Example 4. Additional Functional Characterization of Human PD-1-Fc-OX40L

The previous data indicated that SL-279252 binds to immobilized targets at low nanomolar affinities and was detectable by multiple protein assays. Additional analysis was carried out to determine whether SL-279252 could bind its targets on the surface of living cells in vitro. To assess SL-279252 binding to the human OX40 receptor, the human AML T cell line Jurkat was engineered to overexpress OX40, creating Jurkat/hOX40 cells (verified by flow cytometry; FIG. 15, panel A). To assess binding to PD-L1, the Chinese hamster ovary cell line, CHO-K1, which does not express human PD-L1, was transfected to stably express human PD-L1 (FIG. 15, panel B). To assess binding to human CD47, CHO-K1 cells were transfected to stably express human CD47 (FIG. 15, panel C).

CHO-K1 or CHO-K1-PD-L1 cells were then treated with increasing amounts of SL-279252 and analyzed by flow cytometry for the detection of the human OX40L domain using anti-human OX40L-APC antibodies. SL-279252 did not bind to parental CHO-K1 cells since they expressed no detectable human PD-L1. However, nearly the entire population of CHO-K1-PD-L1 cells shifted significantly, indicating that the human PD1 component of SL-279252 was capable of binding its receptor on living cells (FIG. 15, panel D). Jurkat or Jurkat/OX40 cells were then treated with increasing amounts of SL-279252 and analyzed by flow cytometry for detection of the human OX40L domain using anti-human OX40L-APC antibodies. SL-279252 did not bind parental Jurkat cells with high efficiency, since they express low amounts of human OX40. However, nearly the entire population of Jurkat/OX40 cells shifted significantly, indicating that the human OX40L component of SL-279252 was capable of binding its receptor on living cells (FIG. 15, panel E).

To investigate binding of another chimeric fusion protein, human CD172a-Fc-OX40L, CHO-K1 or CHO-K1-CD47 cells were then treated with increasing amounts of CD172a-Fc-OX40L and analyzed by flow cytometry for the detection of the human OX40L domain using anti-human OX40L-APC antibodies. CD172a-Fc-OX40L did not bind to parental CHO-K1 cells since they expressed no detectable human CD47. However, nearly the entire population of CHO-K1-PD-L1 cells shifted significantly, indicating that the human CD172a component of CD172a-Fc-OX40L was capable of binding its receptor on living cells (FIG. 15, panel F). Jurkat or Jurkat/OX40 cells were then treated with increasing amounts of CD172a-Fc-OX40L and analyzed by flow cytometry for detection of the human OX40L domain using anti-human OX40L-APC antibodies. CD172a-Fc-OX40L did not bind parental Jurkat cells with high efficiency, since they express low amounts of human OX40. However, nearly the entire population of Jurkat/OX40 cells shifted significantly, indicating that the human OX40L component of CD172a-Fc-OX40L was capable of binding its receptor on living cells (FIG. 15, panel G).

Additionally, a number of human tumor cell lines were screened for differing levels of endogenous human PD-L1 expression by flow cytometry. A prostate cancer cell line (PC3) as PD-L1_(low) and a lung adenocarcinoma cell line (HCC827) as PD-L1_(high) were identified (FIG. 15, panel H). The PC3 and HCC827 cells were incubated with increasing amounts of SL-279252, and binding was detected using flow cytometry. SL-279252 did not bind to PC3 cells (PD-L1_(low)) efficiently (FIG. 15, panel I). However, SL-279252 bound significantly to HCC827 cells (PD-L1_(high)) in a concentration dependent manner (FIG. 15, panel J). This clearly indicated that SL-279252 could bind both human OX40 and PD-L1 expressed on the cell surface, which provided compelling evidence for its dual binding functionality.

To expand upon these results, experiments were performed SL-279252 binding to primary T cells isolated from peripheral blood mononuclear cells (PBMCs), induced for 2 days ex vivo with a chemical combination known to stimulate OX40 expression (phorbol 12-myristate 13-acetate; PMA, phytohemagglutinin; PHA, and lonomycin). As expected, a large increase in OX40 expression on CD4+ and CD8+ T cells was observed following PMA/PHA/Ion treatment (FIG. 16, panel A). Binding of SL-279252 to CD4+ and CD8+ cells was confirmed using the methods described above (FIG. 16, panel B). It was noted that SL-279252 bound efficiently to human T cells (both CD4+ and CD8+).

A T cell activation/IL2 release assay was utilized to assess the extent that PD-L1 expression on tumor cells inhibited T cell secretion of the anti-tumorigenic cytokine IL2 when the cells were co-cultured (FIG. 16, panel C). After 2 days, activated T cells were plated on irradiated PD-L1_(low) (PC3) and PD-L1_(high) (HCC827) expressing cancer cell lines in the presence or absence of SL-279252. Various readouts of T cell activation were assessed for up to 1 week following initial T cell isolation, including IL2 secretion (FIG. 16 panel D), proliferation and cytokine expression (FIG. 16, panel E). Baseline levels of IL2 secretion (in the absence of SL-279252) were significantly higher in PD-L1_(low) PC3 co-cultures than with PD-L1_(high) HCC827 cells 6 days after T cell isolation, suggesting that tumor PD-L1 expression either directly or indirectly suppressed the further activation of T cells, as determined by IL2 secretion (FIG. 16, panel D). The addition of SL-279252 to both PC3 and HCC827 co-cultures increased the IL2 secretion in a concentration dependent manner. Specifically, the observed increase in IL-2 from HCC827 co-cultures (PD-L1_(high)) from baseline (no SL-279252) to 5 ug/mL of SL-279252 was 1.92-fold, compared to 1.27-fold when co-cultured with PC3 cells (PD-L1low).

Furthermore, additional characteristics of T cell activation were analyzed, including expression of the proliferation marker Ki67 (FIG. 16, panel E; top). Co-culture of activated T cells with PD-L1_(high) HCC827 cells inhibited proliferation as compared to the level observed in the absence of HCC827 cells (black line). The addition of SL-279252 to the co-culture increased Ki67 staining in both CD4+ and CD8+ T cells. Moreover, activated T cells expressed higher levels of the cytokines IFNγ and TNFα when co-cultured on HCC827 cells than when T cells were cultured alone, possibly due to the secretion of other stimulatory factors by the tumor cells (FIG. 16, panel E; bottom). The expression of these cytokines increased significantly following treatment with SL-279252.

Altogether these data demonstrate, inter alia, that SL-279252 bound tightly to its partners PD-L1 and OX40 and was able to reverse PD-L1 mediated T cell inhibition by PD-L1 positive human tumor cells in vitro.

Example 5. Construction and Characterization of Additional Chimeric Proteins

Additional constructs were generated which include: additional human PD-1-Fc-OX40L constructs as well as human hCD172a-Fc-OX40L, hPD1-Fc-TL1A, hBTLA-Fc-OX40L, hTMIGD2-Fc-OX40L, hTIM3-Fc-OX40L, mPD1-Fc-GITRL, mPD1-Fc-41BBL, mPD1-Fc-TL1A, mCD172a-Fc-CD40L, hTIGIT-Fc-OX40L and canine PD-1-Fc-OX40L. Each of these constructs was codon optimized for expression in Chinese Hamster Ovary (CHO) cells, transfected into CHO cells and individual clones were selected for high expression. High expressing clones were then used for small-scale manufacturing in stirred bioreactors in serum-free media and the relevant chimeric fusion proteins were purified with Protein A binding resin columns. FIG. 17, panel A shows a Western blot characterization of various chimeric proteins including hCD172a-Fc-OX40L, hPD1-Fc-TL1A, hBTLA-Fc-OX40L, hTMIGD2-Fc-OX40L, hTIM3-Fc-OX40L, mPD1-Fc-GITRL, mPD1-Fc-41BBL, mPD1-Fc-TL1A, mCD172a-Fc-CD40L, hTIGIT-Fc-OX40L.

Binding assays were carried out to characterize the ability of the various human ECD-Fc-OX40L constructs to bind to hOX40. With respect to hX_(ECD)-Fc-OX40L, X refers to the ECD of each protein listed in the bracket on the left (with reference to FIG. 17, panel B). Panel B of FIG. 17 shows a schematic representation of the ELISA method used to detect binding of hX_(ECD)-Fc-OX40L to hOX40. Recombinant hOX40 fused to human Fc (hOX40-hFc) was used to capture hX_(ECD)-Fc-OX40L in the culture media. Because the hOX40 fusion protein used to capture the target fusion proteins also contains a hIgG region, blocking was performed using a non-HRP conjugated anti-hIgG prior to incubation with the culture supernatants containing the target fusion proteins. A rabbit polyclonal antibody to hIgG was used to detect the hIgG domain in the chimeric protein and subsequently detected using a horseradish peroxidase (HRP)-conjugated polyclonal antibody to rabbit IgG (H+L).

The binding of SL-279252 to cell surface expressed OX40 on Jurkat cells by flow cytometry was compared to two negative control proteins which are not expected to bind human OX40. These data demonstrate that SL-279252 efficiently binds human OX40 (left panel), while neither human PD1-Fc-TL1A or canine PD1-Fc-OX40L were observed to bind human OX40 (FIG. 17, panel C).

The human CD172a-Fc-OX40L construct was imported into the protein tertiary prediction software RaptorX to determine the tertiary structure. The predicted tertiary structure is shown in FIG. 17, panel D.

The codon-optimized DNA sequence of several chimeric fusion proteins were synthesized and directionally cloned into pVITRO2, pcDNA3.4 and other expression vectors. Vectors were then either transiently or stably transfected into CHO or 293 cells and individual clones were selected for high expression. For example, SL-279252 was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel E).

In another example, CD172a-Fc-OX40L was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel F). In another example, CD172a-Fc-CD40L was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by the Perkin Elmer LabChip system and quantitated as compared to a BCG standard (FIG. 17, panel G). In another example, human TIGIT-Fc-OX40L was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel H).

The binding affinity of human CD172a-Fc-OX40L was evaluated by surface plasmon resonance (SPR) analysis to hCD47, hOX40 and various human Fc receptors (FIG. 17, panels I-M). Specifically, polyhistidine-tagged versions of recombinant human CD47 and human OX40 was bound to ProteOn HTG tris-NTA chips (BIORAD). CD172a-Fc-OX40L was then flowed over the bound ligands over a time course and a relative index of ‘on-rate’ (Ka) and ‘off-rate’ (Kd) was generated to calculate binding affinity (K_(D)) of CD172a-Fc-OX40L to each partner. Recombinant human CD47-Fc and OX40L-Fc were used as positive controls for binding. These controls have a relatively fast ‘on-rate’ and an equally fast ‘off-rate’, resulting in low nanomolar binding affinities. Consistent with these results, the ‘on-rate’ of CD172a-Fc-OX40L to human CD47 was rapid, however the ‘off-rate’ was much lower, in fact ˜40-fold slower than the ‘off-rate’ of recombinant CD47-Fc, indicating that CD172a-Fc-OX40L bound quickly and stably, with long on-target residence time (FIG. 17, panel I). The K_(D) of CD172a-Fc-OX40L binding to human CD47 was calculated to be 3.59 nM. CD172a-Fc-OX40L bound with high affinity to human OX40 (869 pM), again with a fast ‘on-rate’ and slow ‘off-rate’ (FIG. 17, panel J).

To further define the molecular characteristics of CD172a-Fc-OX40L, SPR was performed, analyzing the binding affinities of CD172a-Fc-OX40L to chip-bound, Fcγ receptors FcγR1A and to the neonatal receptor, FcRn. The human immunoglobulin IgG1 was shown to bind with the highest affinities to FcγR1A, followed by FcRn, in addition to low-level binding to FcγR2b (FIG. 17, panel K and L). CD172a-Fc-OX40L did not bind to FcγR1A or FcγR2B, but did bind to FcRn at 790 nM affinity (FIG. 17, panel L). Without wishing to be bound by theory, this binding characteristic may be important to the fusion protein because FcRn is involved in IgG recycling to the surface of a cell, thereby avoiding lysosomal degradation, and potentially extending the in vivo half-life of CD172a-Fc-OX40L. Summary data for CD172a-Fc-OX40L binding affinities are including (FIG. 17, panel M).

The codon-optimized DNA sequence of several additional chimeric fusion proteins were synthesized and directionally cloned into pVITRO2, pcDNA3.4 and other expression vectors. Vectors were then either transiently or stably transfected into CHO or 293 cells and individual clones were selected for high expression. For example, canine PD1-Fc-OX40L was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel N). In another example, mouse PD1-Fc-OX40L was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel O). In another example, mouse PD1-Fc-GITRL was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel P). In another example, mouse PD1-Fc-41BBL was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel Q). In another example, mouse PD1-Fc-TL1A was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel R). In yet another example, CD115-Fc-CD40L was produced from a transient transfection from 293 cells, purified by affinity chromatography to Protein A columns and evaluated by Coomassie staining, Western blot and quantitated as compared to a BCG standard (FIG. 17, panel S). Each purified protein is characterized by ELISA assays to bind to the marker, e.g. the intended inhibitory ligand as well as the intended costimulatory receptor. For example, to test the binding of purified human PD-1-Fc-OX40L, recombinant PD-L1-Fc is adsorbed to microtiter plates and used to capture PD-1-Fc-OX40L. Any bound PD-1-Fc-OX40L is then detected by using recombinant human OX40-Fc linked to biotin, which is then detected in a chromogenic assay through binding with streptravidin-HRP.

In addition, each purified protein has been characterized by flow cytometry to bind the intended inhibitory ligand as well as the intended costimulatory receptor. For example, human tumor cell lines are characterized for endogenous expression of PD-L1, which was found to be particularly abundant on several human melanoma tumor cell lines. These same tumor cell lines were shown to be negative for human OX40L. Following incubation with PD-1-Fc-OX40L, any bound chimeric fusion protein is detected with human OX40L specific antibodies. Similarly, human Jurkat cells were transfected with human OX40 and shown to be negative for human PD-L1. Following incubation with the chimeric PD-1-Fc-OX40L constructs, any bound complex is detected using anti-human PD-L1 specific antibodies. A series of screening cell lines were generated in order to detect specific cell surface binding of each chimeric fusion protein to its respective receptor/ligand, these included: CHO-K1-CD47, CHO-K1-PD-L1, CHO-K1-HVEM, CHO-K1-HHLA2, CHO-K1-VISTA, CHO-K1-Gal9, HeLa-PD-L1, HeLa-CD47, HeLa-HVEM, HeLa-HHLA2, HeLa-VISTA, HeLa-Gal9.

To determine the functional activity of each receptor, in vitro T cell proliferation assays are performed in the presence of inhibitory ligand positive human tumor cells. For example, human melanoma tumor cells expressing PD-L1 are pulsed with peptides specific for hen egg lysozyme (HEL) and incubated with human HEL specific T cells expressing OX40 receptor. The proliferation of these cells is monitored in the presence and absence of the PD-1-Fc-OX40L construct and found to be functionally responsive to the presence of the chimeric constructs. In a similar system, human tumors expressing HVEM, CD47, galectin-9, TIGIT receptors or TMIGD2 receptors are used.

In some experiments, mouse PD-1-Fc-OX40L or mouse PD-1-Fc-TL1A are used to treat murine tumors known to be positive for murine PD-L1 (including B16-F10 melanoma, MC38 colon carcinoma and CT26 colon carcinoma). In these systems, established tumors are treated with purified chimeric fusion proteins as compared to PD-1-Fc fusion proteins, anti-PD-1 or anti-PD-L1 monoclonal antibodies or anti-OX40 or anti-GITR monoclonal antibodies. In these experiments, the activity of the chimeric constructs is observed to lead to enhanced antigen-specific T cell responses and increased rates of tumor rejection as compared to the individual therapeutics. In some experiments, nucleic acid constructs encoding PD-1-Fc-OX40L or PD-1-Fc-TL1A are directly electroporated into established tumors. In these experiments, the chimeric constructs are shown to lead to increased rates of tumor rejection as well as increased tumor antigen specific CD8+ T cell proliferation detected both in the peripheral blood and within established tumors.

To determine the binding of purified chimeric fusion proteins to human tumor explants, fresh frozen human tumor samples are obtained and incubated with each chimeric fusion protein. Any bound fusion protein is detected with anti-human OX40L and controlled against background staining by separate staining with anti-human OX40L.

To determine the molecular characteristics of each fusion protein, purified chimeric fusion proteins are characterized by size exclusion chromatography. This analysis is important because, for example, the OX40L ECD is known to form a homo-trimer, while the Fc region is known to form a homo-dimer, while the inhibitory ligand binding receptor may either be monomeric (e.g. PD-1) or form homo-multimers (e.g. TIM3). Thus, there are several possibilities for the individual species that may be formed by these chimeric constructs. Further molecular characterization by mass spec, thermal stability, pH stability, physical stability, charge profile, hydrophobicity, physical stability, buffer compatibility and solubility up to 100 mg/mL are also performed.

TABLE 1 Illustrative human Type I proteins which may be incorporated into the present compositions and methods include (as used herein “Entry” refers to the human Type I protein entry in the Uniprot database and “Entry name” refers to the human Type I protein entry in the Uniprot database). Entry Entry name Protein names Gene names Length P04439 1A03_HUMAN HLA class I histocompatibility antigen, A-3 alpha chain (MHC class I antigen A*3) HLA-A HLAA 365 P30456 1A43_HUMAN HLA class I histocompatibility antigen, A-43 alpha chain (Aw-43) (MHC class I antigen HLA-A HLAA 365 A*43) P10316 1A69_HUMAN HLA class I histocompatibility antigen, A-69 alpha chain (Aw-69) (HLA class I HLA-A HLAA 365 histocompatibility antigen, A-28 alpha chain) (MHC class I antigen A*69) P30460 1B08_HUMAN HLA class I histocompatibility antigen, B-8 alpha chain (MHC class I antigen B*8) HLA-B HLAB 362 Q95365 1B38_HUMAN HLA class I histocompatibility antigen, B-38 alpha chain (Bw-4) (MHC class I antigen HLA-B HLAB 362 B*38) P18464 1B51_HUMAN HLA class I histocompatibility antigen, B-51 alpha chain (MHC class I antigen B*51) HLA-B HLAB 362 P30495 1B56_HUMAN HLA class I histocompatibility antigen, B-56 alpha chain (Bw-22) (Bw-56) (MHC class I HLA-B HLAB 362 antigen B*56) P10319 1B58_HUMAN HLA class I histocompatibility antigen, B-58 alpha chain (Bw-58) (MHC class I antigen HLA-B HLAB 362 B*58) P30501 1C02_HUMAN HLA class I histocompatibility antigen, Cw-2 alpha chain (MHC class I antigen Cw*2) HLA-C HLAC 366 P04222 1C03_HUMAN HLA class I histocompatibility antigen, Cw-3 alpha chain (MHC class I antigen Cw*3) HLA-C HLAC 366 Q9TNN7 1C05_HUMAN HLA class I histocompatibility antigen, Cw-5 alpha chain (MHC class I antigen Cw*5) HLA-C HLAC 366 P10321 1C07_HUMAN HLA class I histocompatibility antigen, Cw-7 alpha chain (MHC class I antigen Cw*7) HLA-C HLAC 366 Q07000 1C15_HUMAN HLA class I histocompatibility antigen, Cw-15 alpha chain (MHC class I antigen Cw*15) HLA-C HLAC 366 Q95604 1C17_HUMAN HLA class I histocompatibility antigen, Cw-17 alpha chain (MHC class I antigen Cw*17) HLA-C D6S204 372 HLA-JY3 HLAC P13760 2B14_HUMAN HLA class II histocompatibility antigen, DRB1-4 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*4) (DR-4) (DR4) Q9TQE0 2B19_HUMAN HLA class II histocompatibility antigen, DRB1-9 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*9) (DR-9) (DR9) Q30167 2B1A_HUMAN HLA class II histocompatibility antigen, DRB1-10 beta chain (DRw10) (MHC class II HLA-DRB1 266 antigen DRB1*10) Q29974 2B1G_HUMAN HLA class II histocompatibility antigen, DRB1-16 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*16) (DR-16) (DR16) P01889 1B07_HUMAN HLA class I histocompatibility antigen, B-7 alpha chain (MHC class I antigen B*7) HLA-B HLAB 362 P30462 1B14_HUMAN HLA class I histocompatibility antigen, B-14 alpha chain (MHC class I antigen B*14) HLA-B HLAB 362 P30464 1B15_HUMAN HLA class I histocompatibility antigen, B-15 alpha chain (MHC class I antigen B*15) HLA-B HLAB 362 P03989 1B27_HUMAN HLA class I histocompatibility antigen, B-27 alpha chain (MHC class I antigen B*27) HLA-B HLAB 362 P18463 1B37_HUMAN HLA class I histocompatibility antigen, B-37 alpha chain (MHC class I antigen B*37) HLA-B HLAB 362 P30479 1B41_HUMAN HLA class I histocompatibility antigen, B-41 alpha chain (Bw-41) (MHC class I antigen HLA-B HLAB 362 B*41) P30483 1B45_HUMAN HLA class I histocompatibility antigen, B-45 alpha chain (Bw-45) (MHC class I antigen HLA-B HLAB 362 B*45) P30485 1B47_HUMAN HLA class I histocompatibility antigen, B-47 alpha chain (Bw-47) (MHC class I antigen HLA-B HLAB 362 B*47) P30487 1B49_HUMAN HLA class I histocompatibility antigen, B-49 alpha chain (HLA class I histocompatibility HLA-B HLAB 362 antigen, B-21 alpha chain) (MHC class I antigen B*49) P30491 1B53_HUMAN HLA class I histocompatibility antigen, B-53 alpha chain (Bw-53) (MHC class I antigen HLA-B HLAB 362 B*53) Q29940 1B59_HUMAN HLA class I histocompatibility antigen, B-59 alpha chain (MHC class I antigen B*59) HLA-B HLAB 362 P30498 1B78_HUMAN HLA class I histocompatibility antigen, B-78 alpha chain (MHC class I antigen B*78) HLA-B HLAB 362 P30499 1C01_HUMAN HLA class I histocompatibility antigen, Cw-1 alpha chain (MHC class I antigen Cw*1) HLA-C HLAC 366 P30505 1C08_HUMAN HLA class I histocompatibility antigen, Cw-8 alpha chain (MHC class I antigen Cw*8) HLA-C HLAC 366 P30508 1C12_HUMAN HLA class I histocompatibility antigen, Cw-12 alpha chain (MHC class I antigen Cw*12) HLA-C HLAC 366 P01912 2B13_HUMAN HLA class II histocompatibility antigen, DRB1-3 chain (Clone P2-beta-3) (MHC class II HLA-DRB1 266 antigen DRB1*3) Q30134 2B18_HUMAN HLA class II histocompatibility antigen, DRB1-8 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*8) (DR-8) (DR8) (DRw8) Q95IE3 2B1C_HUMAN HLA class II histocompatibility antigen, DRB1-12 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*12) (DR-12) (DR12) Q9BYF1 ACE2_HUMAN Angiotensin-converting enzyme 2 (EC 3.4.17.23) (ACE-related carboxypeptidase) ACE2 805 (Angiotensin-converting enzyme homolog) (ACEH) (Metalloprotease MPROT15) UNQ868/PRO1885 [Cleaved into: Processed angiotensin-converting enzyme 2] P16188 1A30_HUMAN HLA class I histocompatibility antigen, A-30 alpha chain (MHC class I antigen A*30) HLA-A HLAA 365 P16190 1A33_HUMAN HLA class I histocompatibility antigen, A-33 alpha chain (Aw-19) (Aw-33) (MHC class I HLA-A HLAA 365 antigen A*33) P01891 1A68_HUMAN HLA class I histocompatibility antigen, A-68 alpha chain (Aw-68) (HLA class I HLA-A HLAA 365 histocompatibility antigen, A-28 alpha chain) (MHC class I antigen A*68) Q29836 1B67_HUMAN HLA class I histocompatibility antigen, B-67 alpha chain (MHC class I antigen B*67) HLA-B HLAB 362 P13761 2B17_HUMAN HLA class II histocompatibility antigen, DRB1-7 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*7) (DR-7) (DR7) Q5Y7A7 2B1D_HUMAN HLA class II histocompatibility antigen, DRB1-13 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*13) (DR-13) (DR13) P13746 1A11_HUMAN HLA class I histocompatibility antigen, A-11 alpha chain (MHC class I antigen A*11) HLA-A HLAA 365 P05534 1A24_HUMAN HLA class I histocompatibility antigen, A-24 alpha chain (Aw-24) (HLA class I HLA-A HLAA 365 histocompatibility antigen, A-9 alpha chain) (MHC class I antigen A*24) P30512 1A29_HUMAN HLA class I histocompatibility antigen, A-29 alpha chain (Aw-19) (MHC class I antigen HLA-A HLAA 365 A*29) P16189 1A31_HUMAN HLA class I histocompatibility antigen, A-31 alpha chain (MHC class I antigen A*31) HLA-A HLAA 365 P10314 1A32_HUMAN HLA class I histocompatibility antigen, A-32 alpha chain (MHC class I antigen A*32) HLA-A HLAA 365 Q04826 1B40_HUMAN HLA class I histocompatibility antigen, B-40 alpha chain (Bw-60) (MHC class I antigen HLA-B HLAB 362 B*40) P30484 1B46_HUMAN HLA class I histocompatibility antigen, B-46 alpha chain (Bw-46) (MHC class I antigen HLA-B HLAB 362 B*46) P30486 1B48_HUMAN HLA class I histocompatibility antigen, B-48 alpha chain (Bw-48) (MHC class I antigen HLA-B HLAB 362 B*48) P30490 1B52_HUMAN HLA class I histocompatibility antigen, B-52 alpha chain (Bw-52) (HLA class I HLA-B HLAB 362 histocompatibility antigen, B-5 alpha chain) (MHC class I antigen B*52) Q31612 1B73_HUMAN HLA class I histocompatibility antigen, B-73 alpha chain (MHC class I antigen B*73) HLA-B HLAB 363 Q31610 1B81_HUMAN HLA class I histocompatibility antigen, B-81 alpha chain (B′DT) (MHC class I antigen HLA-B HLAB 362 B*81) Q29960 1C16_HUMAN HLA class I histocompatibility antigen, Cw-16 alpha chain (MHC class I antigen Cw*16) HLA-C HLAC 366 Q29865 1C18_HUMAN HLA class I histocompatibility antigen, Cw-18 alpha chain (MHC class I antigen Cw*18) HLA-C HLAC 366 Q9GIY3 2B1E_HUMAN HLA class II histocompatibility antigen, DRB1-14 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*14) (DR-14) (DR14) P30443 1A01_HUMAN HLA class I histocompatibility antigen, A-1 alpha chain (MHC class I antigen A*1) HLA-A HLAA 365 P01892 1A02_HUMAN HLA class I histocompatibility antigen, A-2 alpha chain (MHC class I antigen A*2) HLA-A HLAA 365 P30447 1A23_HUMAN HLA class I histocompatibility antigen, A-23 alpha chain (HLA class I histocompatibility HLA-A HLAA 365 antigen, A-9 alpha chain) (MHC class I antigen A*23) P18462 1A25_HUMAN HLA class I histocompatibility antigen, A-25 alpha chain (HLA class I histocompatibility HLA-A HLAA 365 antigen, A-10 alpha chain) (MHC class I antigen A*25) P30450 1A26_HUMAN HLA class I histocompatibility antigen, A-26 alpha chain (MHC class I antigen A*26) HLA-A HLAA 365 P30453 1A34_HUMAN HLA class I histocompatibility antigen, A-34 alpha chain (Aw-34) (HLA class I HLA-A HLAA 365 histocompatibility antigen, A-10 alpha chain) (MHC class I antigen A*34) P30457 1A66_HUMAN HLA class I histocompatibility antigen, A-66 alpha chain (Aw-66) (HLA class I HLA-A HLAA 365 histocompatibility antigen, A-10 alpha chain) (MHC class I antigen A*66) Q09160 1A80_HUMAN HLA class I histocompatibility antigen, A-80 alpha chain (Aw-80) (HLA class I HLA-A HLAA 365 histocompatibility antigen, A-1 alpha chain) (MHC class I antigen A*80) P30461 1B13_HUMAN HLA class I histocompatibility antigen, B-13 alpha chain (MHC class I antigen B*13) HLA-B HLAB 362 P30466 1B18_HUMAN HLA class I histocompatibility antigen, B-18 alpha chain (MHC class I antigen B*18) HLA-B HLAB 362 P30685 1B35_HUMAN HLA class I histocompatibility antigen, B-35 alpha chain (MHC class I antigen B*35) HLA-B HLAB 362 P30475 1B39_HUMAN HLA class I histocompatibility antigen, B-39 alpha chain (MHC class I antigen B*39) HLA-B HLAB 362 P30480 1B42_HUMAN HLA class I histocompatibility antigen, B-42 alpha chain (MHC class I antigen B*42) HLA-B HLAB 362 P30481 1B44_HUMAN HLA class I histocompatibility antigen, B-44 alpha chain (Bw-44) (MHC class I antigen HLA-B HLAB 362 B*44) P30488 1B50_HUMAN HLA class I histocompatibility antigen, B-50 alpha chain (Bw-50) (HLA class I HLA-B HLAB 362 histocompatibility antigen, B-21 alpha chain) (MHC class I antigen B*50) P30492 1B54_HUMAN HLA class I histocompatibility antigen, B-54 alpha chain (Bw-22) (Bw-54) (MHC class I HLA-B HLAB 362 antigen B*54) P18465 1B57_HUMAN HLA class I histocompatibility antigen, B-57 alpha chain (Bw-57) (MHC class I antigen HLA-B HLAB 362 B*57) Q29718 1B82_HUMAN HLA class I histocompatibility antigen, B-82 alpha chain (MHC class I antigen B*82) HLA-B HLAB 362 P30504 1C04_HUMAN HLA class I histocompatibility antigen, Cw-4 alpha chain (MHC class I antigen Cw*4) HLA-C HLAC 366 Q29963 1C06_HUMAN HLA class I histocompatibility antigen, Cw-6 alpha chain (MHC class I antigen Cw*6) HLA-C HLAC 366 P30510 1C14_HUMAN HLA class I histocompatibility antigen, Cw-14 alpha chain (MHC class I antigen Cw*14) HLA-C HLAC 366 P04229 2B11_HUMAN HLA class II histocompatibility antigen, DRB1-1 beta chain (MHC class II antigen HLA-DRB1 266 DRB1*1) (DR-1) (DR1) P20039 2B1B_HUMAN HLA class II histocompatibility antigen, DRB1-11 beta chain (DR-5) (DR5) (DRw11) (MHC HLA-DRB1 266 class II antigen DRB1*11) P01911 2B1F_HUMAN HLA class II histocompatibility antigen, DRB1-15 beta chain (DW2.2/DR2.2) (MHC class HLA-DRB1 HLA- 266 II antigen DRB1*15) DRB2 O14672 ADA10_HUMAN Disintegrin and metalloproteinase domain-containing protein 10 (ADAM 10) (EC ADAM10 KUZ 748 3.4.24.81) (CDw156) (Kuzbanian protein homolog) (Mammalian disintegrin- MADM metalloprotease) (CD antigen CD156c) Q13444 ADA15_HUMAN Disintegrin and metalloproteinase domain-containing protein 15 (ADAM 15) (EC 3.4.24.—) ADAM15 MDC15 863 (Metalloprotease RGD disintegrin protein) (Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 15) (MDC-15) (Metargidin) O75077 ADA23_HUMAN Disintegrin and metalloproteinase domain-containing protein 23 (ADAM 23) ADAM23 MDC3 832 (Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 3) (MDC-3) P30455 1A36_HUMAN HLA class I histocompatibility antigen, A-36 alpha chain (Aw-36) (MHC class I antigen HLA-A HLAA 365 A*36) P30459 1A74_HUMAN HLA class I histocompatibility antigen, A-74 alpha chain (Aw-19) (Aw-74) (MHC class I HLA-A HLAA 365 antigen A*74) P30493 1B55_HUMAN HLA class I histocompatibility antigen, B-55 alpha chain (Bw-55) (HLA class I HLA-B HLAB 362 histocompatibility antigen, B-12 alpha chain) (MHC class I antigen B*55) CDABP0067 O43184 ADA12_HUMAN Disintegrin and metalloproteinase domain-containing protein 12 (ADAM 12) (EC 3.4.24.—) ADAM12 MLTN 909 (Meltrin-alpha) UNQ346/PRO545 Q9Y3Q7 ADA18_HUMAN Disintegrin and metalloproteinase domain-containing protein 18 (ADAM 18) ADAM18 TMDC3 739 (Transmembrane metalloproteinase-like, disintegrin-like, and cysteine-rich protein III) UNQ858/PRO1867 (tMDC III) Q9H013 ADA19_HUMAN Disintegrin and metalloproteinase domain-containing protein 19 (ADAM 19) (EC 3.4.24.—) ADAM19 MLTNB 955 (Meltrin-beta) (Metalloprotease and disintegrin dendritic antigen marker) (MADDAM) FKSG34 Q9UKF5 ADA29_HUMAN Disintegrin and metalloproteinase domain-containing protein 29 (ADAM 29) (Cancer/testis ADAM29 820 antigen 73) (CT73) Q8TC27 ADA32_HUMAN Disintegrin and metalloproteinase domain-containing protein 32 (ADAM 32) ADAM32 787 UNQ5982/PRO21340 Q9BZ11 ADA33_HUMAN Disintegrin and metalloproteinase domain-containing protein 33 (ADAM 33) (EC 3.4.24.—) ADAM33 C20orf153 813 UNQ873/PRO1891 P05067 A4_HUMAN Amyloid beta A4 protein (ABPP) (APPI) (APP) (Alzheimer disease amyloid protein) APP A4 AD1 770 (Amyloid precursor protein) (Beta-amyloid precursor protein) (Cerebral vascular amyloid peptide) (CVAP) (PreA4) (Protease nexin-II) (PN-II) [Cleaved into: N-APP; Soluble APP- alpha (S-APP-alpha); Soluble APP-beta (S-APP-beta); C99; Beta-amyloid protein 42 (Beta-APP42); Beta-amyloid protein 40 (Beta-APP40); C83; P3(42); P3(40); C80; Gamma-secretase C-terminal fragment 59 (Amyloid intracellular domain 59) (AICD-59) (AID(59)) (Gamma-CTF(59)); Gamma-secretase C-terminal fragment 57 (Amyloid intracellular domain 57) (AICD-57) (AID(57)) (Gamma-CTF(57)); Gamma-secretase C- terminal fragment 50 (Amyloid intracellular domain 50) (AICD-50) (AID(50)) (Gamma- CTF(50)); C31] P12821 ACE_HUMAN Angiotensin-converting enzyme (ACE) (EC 3.2.1.—) (EC 3.4.15.1) (Dipeptidyl ACE DCP DCP1 1306 carboxypeptidase I) (Kininase II) (CD antigen CD143) [Cleaved into: Angiotensin- converting enzyme, soluble form] Q04771 ACVR1_HUMAN Activin receptor type-1 (EC 2.7.11.30) (Activin receptor type I) (ACTR-I) (Activin receptor- ACVR1 ACVRLK2 509 like kinase 2) (ALK-2) (Serine/threonine-protein kinase receptor R1) (SKR1) (TGF-B superfamily receptor type I) (TSR-I) Q8NER5 ACV1C_HUMAN Activin receptor type-1C (EC 2.7.11.30) (Activin receptor type 1C) (ACTR-IC) (Activin ACVR1C ALK7 493 receptor-like kinase 7) (ALK-7) Q9H2U9 ADAM7_HUMAN Disintegrin and metalloproteinase domain-containing protein 7 (ADAM 7) (Sperm ADAM7 GP83 754 maturation-related glycoprotein GP-83) P36896 ACV1B_HUMAN Activin receptor type-1B (EC 2.7.11.30) (Activin receptor type IB) (ACTR-IB) (Activin ACVR1B ACVRLK4 505 receptor-like kinase 4) (ALK-4) (Serine/threonine-protein kinase receptor R2) (SKR2) ALK4 O75078 ADA11_HUMAN Disintegrin and metalloproteinase domain-containing protein 11 (ADAM 11) ADAM11 MDC 769 (Metalloproteinase-like, disintegrin-like, and cysteine-rich protein) (MDC) P78536 ADA17_HUMAN Disintegrin and metalloproteinase domain-containing protein 17 (ADAM 17) (EC ADAM17 CSVP 824 3.4.24.86) (Snake venom-like protease) (TNF-alpha convertase) (TNF-alpha-converting TACE enzyme) (CD antigen CD156b) Q9P0K1 ADA22_HUMAN Disintegrin and metalloproteinase domain-containing protein 22 (ADAM 22) ADAM22 MDC2 906 (Metalloproteinase-disintegrin ADAM22-3) (Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 2) Q9UKQ2 ADA28_HUMAN Disintegrin and metalloproteinase domain-containing protein 28 (ADAM 28) (EC 3.4.24.—) ADAM28 ADAM23 775 (Epididymal metalloproteinase-like, disintegrin-like, and cysteine-rich protein II) (eMDC II) MDCL (Metalloproteinase-like, disintegrin-like, and cysteine-rich protein L) (MDC-L) Q9UKF2 ADA30_HUMAN Disintegrin and metalloproteinase domain-containing protein 30 (ADAM 30) (EC 3.4.24.—) ADAM30 790 UNQ2509/PRO5997 P19021 AMD_HUMAN Peptidyl-glycine alpha-amidating monooxygenase (PAM) [Includes: Peptidylglycine alpha- PAM 973 hydroxylating monooxygenase (PHM) (EC 1.14.17.3); Peptidyl-alpha-hydroxyglycine alpha-amidating lyase (EC 4.3.2.5) (Peptidylamidoglycolate lyase) (PAL)] Q86SJ2 AMGO2_HUMAN Amphoterin-induced protein 2 (AMIGO-2) (Alivin-1) (Differentially expressed in gastric AMIGO2 ALI1 522 adenocarcinomas) (DEGA) Q16671 AMHR2_HUMAN Anti-Muellerian hormone type-2 receptor (EC 2.7.11.30) (Anti-Muellerian hormone type II AMHR2 AMHR 573 receptor) (AMH type II receptor) (MIS type II receptor) (MISRII) (MRII) MISR2 P37023 ACVL1_HUMAN Serine/threonine-protein kinase receptor R3 (SKR3) (EC 2.7.11.30) (Activin receptor-like ACVRL1 ACVRLK1 503 kinase 1) (ALK-1) (TGF-B superfamily receptor type I) (TSR-I) ALK1 Q13443 ADAM9_HUMAN Disintegrin and metalloproteinase domain-containing protein 9 (ADAM 9) (EC 3.4.24.—) ADAM9 KIAA0021 819 (Cellular disintegrin-related protein) (Meltrin-gamma) MCMP MDC9 (Metalloprotease/disintegrin/cysteine-rich protein 9) (Myeloma cell metalloproteinase) MLTNG O43506 ADA20_HUMAN Disintegrin and metalloproteinase domain-containing protein 20 (ADAM 20) (EC 3.4.24.—) ADAM20 726 Q9UKJ8 ADA21_HUMAN Disintegrin and metalloproteinase domain-containing protein 21 (ADAM 21) (EC 3.4.24.—) ADAM21 722 Q99965 ADAM2_HUMAN Disintegrin and metalloproteinase domain-containing protein 2 (ADAM 2) (Cancer/testis ADAM2 FTNB 735 antigen 15) (CT15) (Fertilin subunit beta) (PH-30) (PH30) (PH30-beta) P78325 ADAM8_HUMAN Disintegrin and metalloproteinase domain-containing protein 8 (ADAM 8) (EC 3.4.24.—) ADAM8 MS2 824 (Cell surface antigen MS2) (CD antigen CD156a) Q9H6X2 ANTR1_HUMAN Anthrax toxin receptor 1 (Tumor endothelial marker 8) ANTXR1 ATR 564 TEM8 P58335 ANTR2_HUMAN Anthrax toxin receptor 2 (Capillary morphogenesis gene 2 protein) (CMG-2) ANTXR2 CMG2 489 Q86WK6 AMGO1_HUMAN Amphoterin-induced protein 1 (AMIGO-1) (Alivin-2) AMIGO1 ALI2 493 AMIGO KIAA1163 P16066 ANPRA_HUMAN Atrial natriuretic peptide receptor 1 (EC 4.6.1.2) (Atrial natriuretic peptide receptor type A) NPR1 ANPRA 1061 (ANP-A) (ANPR-A) (NPR-A) (Guanylate cyclase A) (GC-A) Q6UXC1 AEGP_HUMAN Apical endosomal glycoprotein (MAM domain-containing protein 4) MAMDC4 AEGP 1216 UNQ3001/PRO9742 Q9BXJ7 AMNLS_HUMAN Protein amnionless AMN 453 UNQ513/PRO1028 P20594 ANPRB_HUMAN Atrial natriuretic peptide receptor 2 (EC 4.6.1.2) (Atrial natriuretic peptide receptor type B) NPR2 ANPRB 1047 (ANP-B) (ANPR-B) (NPR-B) (Guanylate cyclase B) (GC-B) Q8J025 APCD1_HUMAN Protein APCDD1 (Adenomatosis polyposis coli down-regulated 1 protein) APCDD1 DRAPC1 514 FP7019 P51693 APLP1_HUMAN Amyloid-like protein 1 (APLP) (APLP-1) [Cleaved into: C30] APLP1 650 Q9UM73 ALK_HUMAN ALK tyrosine kinase receptor (EC 2.7.10.1) (Anaplastic lymphoma kinase) (CD antigen ALK 1620 CD246) A6NF34 ANTRL_HUMAN Anthrax toxin receptor-like ANTXRL 631 Q86WK7 AMGO3_HUMAN Amphoterin-induced protein 3 (AMIGO-3) (Alivin-3) AMIGO3 ALI3 504 KIAA1851 UNQ6084/PRO20089 P17342 ANPRC_HUMAN Atrial natriuretic peptide receptor 3 (Atrial natriuretic peptide clearance receptor) (Atrial NPR3 ANPRC 541 natriuretic peptide receptor type C) (ANP-C) (ANPR-C) (NPR-C) C5orf23 NPRC Q06481 APLP2_HUMAN Amyloid-like protein 2 (APLP-2) (APPH) (Amyloid protein homolog) (CDEI box-binding APLP2 APPL2 763 protein) (CDEBP) Q13705 AVR2B_HUMAN Activin receptor type-2B (EC 2.7.11.30) (Activin receptor type IIB) (ACTR-IIB) ACVR2B 512 P35613 BASI_HUMAN Basigin (5F7) (Collagenase stimulatory factor) (Extracellular matrix metalloproteinase BSG 385 inducer) (EMMPRIN) (Leukocyte activation antigen M6) (OK blood group antigen) (Tumor UNQ6505/PRO21383 cell-derived collagenase stimulatory factor) (TCSF) (CD antigen CD147) P50895 BCAM_HUMAN Basal cell adhesion molecule (Auberger B antigen) (B-CAM cell surface glycoprotein) BCAM LU MSK19 628 (F8/G253 antigen) (Lutheran antigen) (Lutheran blood group glycoprotein) (CD antigen CD239) O75882 ATRN_HUMAN Attractin (DPPT-L) (Mahogany homolog) ATRN KIAA0548 1429 MGCA Q9Y5Z0 BACE2_HUMAN Beta-secretase 2 (EC 3.4.23.45) (Aspartic-like protease 56 kDa) (Aspartyl protease 1) BACE2 AEPLC 518 (ASP1) (Asp 1) (Beta-site amyloid precursor protein cleaving enzyme 2) (Beta-site APP ALP56 ASP21 cleaving enzyme 2) (Down region aspartic protease) (DRAP) (Memapsin-1) (Membrane- CDA13 associated aspartic protease 1) (Theta-secretase) UNQ418/PRO852 Q13145 BAMBI_HUMAN BMP and activin membrane-bound inhibitor homolog (Non-metastatic gene A protein) BAMBI NMA 260 (Putative transmembrane protein NMA) P36894 BMR1A_HUMAN Bone morphogenetic protein receptor type-1A (BMP type-1A receptor) (BMPR-1A) (EC BMPR1A ACVRLK3 532 2.7.11.30) (Activin receptor-like kinase 3) (ALK-3) (Serine/threonine-protein kinase ALK3 receptor R5) (SKR5) (CD antigen CD292) P56817 BACE1_HUMAN Beta-secretase 1 (EC 3.4.23.46) (Aspartyl protease 2) (ASP2) (Asp 2) (Beta-site amyloid BACE1 BACE 501 precursor protein cleaving enzyme 1) (Beta-site APP cleaving enzyme 1) (Memapsin-2) KIAA1149 (Membrane-associated aspartic protease 2) Q5VV63 ATRN1_HUMAN Attractin-like protein 1 ATRNL1 KIAA0534 1379 P27037 AVR2A_HUMAN Activin receptor type-2A (EC 2.7.11.30) (Activin receptor type IIA) (ACTR-IIA) (ACTRIIA) ACVR2A ACVR2 513 Q9BWV1 BOC_HUMAN Brother of CDO (Protein BOC) BOC 1114 UNQ604/PRO1190 O00238 BMR1B_HUMAN Bone morphogenetic protein receptor type-1B (BMP type-1B receptor) (BMPR-1B) (EC BMPR1B 502 2.7.11.30) (CD antigen CDw293) O00481 BT3A1_HUMAN Butyrophilin subfamily 3 member A1 (CD antigen CD277) BTN3A1 BTF5 513 Q7Z6A9 BTLA_HUMAN B- and T-lymphocyte attenuator (B- and T-lymphocyte-associated protein) (CD antigen BTLA 289 CD272) Q96KV6 BT2A3_HUMAN Putative butyrophilin subfamily 2 member A3 BTN2A3P BTN2A3 586 P78410 BT3A2_HUMAN Butyrophilin subfamily 3 member A2 BTN3A2 BT3.2 334 BTF3 BTF4 Q6UXE8 BTNL3_HUMAN Butyrophilin-like protein 3 (Butyrophilin-like receptor) BTNL3 BTNLR 466 COLF4100 UNQ744/PRO1472 Q6UXG8 BTNL9_HUMAN Butyrophilin-like protein 9 BTNL9 535 UNQ1900/PRO4346 Q5SY80 CA101_HUMAN Uncharacterized protein C1orf101 C1orf101 951 F2Z333 CA233_HUMAN Fibronectin type-III domain-containing transmembrane protein C1orf233 C1orf233 226 Q13410 BT1A1_HUMAN Butyrophilin subfamily 1 member A1 (BT) BTN1A1 BTN 526 Q8WVV5 BT2A2_HUMAN Butyrophilin subfamily 2 member A2 BTN2A2 BT2.2 523 BTF2 O00478 BT3A3_HUMAN Butyrophilin subfamily 3 member A3 BTN3A3 BTF3 584 Q6UX41 BTNL8_HUMAN Butyrophilin-like protein 8 BTNL8 500 UNQ702/PRO1347 Q6UWJ8 C16L2_HUMAN CD164 sialomucin-like 2 protein CD164L2 174 UNQ6122/PRO20044 P55289 CAD12_HUMAN Cadherin-12 (Brain cadherin) (BR-cadherin) (Neural type cadherin 2) (N-cadherin 2) CDH12 794 Q9UJ99 CAD22_HUMAN Cadherin-22 (Pituitary and brain cadherin) (PB-cadherin) CDH22 C20orf25 828 Q9H251 CAD23_HUMAN Cadherin-23 (Otocadherin) CDH23 KIAA1774 3354 KIAA1812 UNQ1894/PRO4340 Q8IXH8 CAD26_HUMAN Cadherin-like protein 26 (Cadherin-like protein VR20) CDH26 852 P19022 CADH2_HUMAN Cadherin-2 (CDw325) (Neural cadherin) (N-cadherin) (CD antigen CD325) CDH2 CDHN NCAD 906 P55285 CADH6_HUMAN Cadherin-6 (Kidney cadherin) (K-cadherin) CDH6 790 Q9ULB5 CADH7_HUMAN Cadherin-7 CDH7 CDH7L1 785 P55286 CADH8_HUMAN Cadherin-8 CDH8 799 Q9ULX7 CAH14_HUMAN Carbonic anhydrase 14 (EC 4.2.1.1) (Carbonate dehydratase XIV) (Carbonic anhydrase CA14 337 XIV) (CA-XIV) UNQ690/PRO1335 Q5VU97 CAHD1_HUMAN VWFA and cache domain-containing protein 1 (Cache domain-containing protein 1) CACHD1 KIAA1573 1274 VWCD1 P27824 CALX_HUMAN Calnexin (IP90) (Major histocompatibility complex class I antigen-binding protein p88) CANX 592 (p90) Q13873 BMPR2_HUMAN Bone morphogenetic protein receptor type-2 (BMP type-2 receptor) (BMPR-2) (EC BMPR2 PPH1 1038 2.7.11.30) (Bone morphogenetic protein receptor type II) (BMP type II receptor) (BMPR- II) Q7KYR7 BT2A1_HUMAN Butyrophilin subfamily 2 member A1 BTN2A1 BT2.1 527 BTF1 P35070 BTC_HUMAN Probetacellulin [Cleaved into: Betacellulin (BTC)] BTC 178 Q86VB7 C163A_HUMAN Scavenger receptor cysteine-rich type 1 protein M130 (Hemoglobin scavenger receptor) CD163 M130 1156 (CD antigen CD163) [Cleaved into: Soluble CD163 (sCD163)] Q8TCZ2 C99L2_HUMAN CD99 antigen-like protein 2 (MIC2-like protein 1) (CD antigen CD99) CD99L2 MIC2L1 262 UNQ1964/PRO4486 Q8IZS8 CA2D3_HUMAN Voltage-dependent calcium channel subunit alpha-2/delta-3 (Voltage-gated calcium CACNA2D3 1091 channel subunit alpha-2/delta-3) [Cleaved into: Voltage-dependent calcium channel subunit alpha-2-3; Voltage-dependent calcium channel subunit delta-3] Q7Z3S7 CA2D4_HUMAN Voltage-dependent calcium channel subunit alpha-2/delta-4 (Voltage-gated calcium CACNA2D4 1137 channel subunit alpha-2/delta-4) [Cleaved into: Voltage-dependent calcium channel subunit alpha-2-4; Voltage-dependent calcium channel subunit delta-4] Q9Y6N8 CAD10_HUMAN Cadherin-10 (T2-cadherin) CDH10 788 Q12864 CAD17_HUMAN Cadherin-17 (Intestinal peptide-associated transporter HPT-1) (Liver-intestine cadherin) CDH17 832 (LI-cadherin) P55283 CADH4_HUMAN Cadherin-4 (Retinal cadherin) (R-CAD) (R-cadherin) CDH4 916 P33151 CADH5_HUMAN Cadherin-5 (7B4 antigen) (Vascular endothelial cadherin) (VE-cadherin) (CD antigen CDH5 784 CD144) Q8NFZ8 CADM4_HUMAN Cell adhesion molecule 4 (Immunoglobulin superfamily member 4C) (IgSF4C) (Nectin-like CADM4 IGSF4C 388 protein 4) (NECL-4) (TSLC1-like protein 2) NECL4 TSLL2 Q9NPY3 C1QR1_HUMAN Complement component C1q receptor (C1q/MBL/SPA receptor) (C1qR) (C1qR(p)) CD93 C1QR1 652 (C1qRp) (CDw93) (Complement component 1 q subcomponent receptor 1) (Matrix- MXRA4 remodeling-associated protein 4) (CD antigen CD93) Q9NY47 CA2D2_HUMAN Voltage-dependent calcium channel subunit alpha-2/delta-2 (Voltage-gated calcium CACNA2D2 1150 channel subunit alpha-2/delta-2) [Cleaved into: Voltage-dependent calcium channel KIAA0558 subunit alpha-2-2; Voltage-dependent calcium channel subunit delta-2] Q8N3J6 CADM2_HUMAN Cell adhesion molecule 2 (Immunoglobulin superfamily member 4D) (IgSF4D) (Nectin-like CADM2 IGSF4D 435 protein 3) (NECL-3) (Synaptic cell adhesion molecule 2) (SynCAM 2) NECL3 Q13634 CAD18_HUMAN Cadherin-18 (Cadherin-14) CDH18 CDH14 790 A8MVZ5 BTNLA_HUMAN Butyrophilin-like protein 10 BTNL10 291 Q9NR16 C163B_HUMAN Scavenger receptor cysteine-rich type 1 protein M160 (CD163 antigen-like 1) (CD antigen CD163L1 CD163B 1453 CD163b) M160 UNQ6434/PRO23202 P54289 CA2D1_HUMAN Voltage-dependent calcium channel subunit alpha-2/delta-1 (Voltage-gated calcium CACNA2D1 1103 channel subunit alpha-2/delta-1) [Cleaved into: Voltage-dependent calcium channel CACNL2A CCHL2A subunit alpha-2-1; Voltage-dependent calcium channel subunit delta-1] MHS3 Q86UP0 CAD24_HUMAN Cadherin-24 CDH24 CDH11L 819 UNQ2834/PRO34009 Q9BY67 CADM1_HUMAN Cell adhesion molecule 1 (Immunoglobulin superfamily member 4) (IgSF4) (Nectin-like CADM1 IGSF4 442 protein 2) (NECL-2) (Spermatogenic immunoglobulin superfamily) (SgIgSF) (Synaptic cell IGSF4A NECL2 adhesion molecule) (SynCAM) (Tumor suppressor in lung cancer 1) (TSLC-1) SYNCAM TSLC1 Q9HBT6 CAD20_HUMAN Cadherin-20 CDH20 CDH7L3 801 Q16790 CAH9_HUMAN Carbonic anhydrase 9 (EC 4.2.1.1) (Carbonate dehydratase IX) (Carbonic anhydrase IX) CA9 G250 MN 459 (CA-IX) (CAIX) (Membrane antigen MN) (P54/58N) (Renal cell carcinoma-associated antigen G250) (RCC-associated antigen G250) (pMW1) O75976 CBPD_HUMAN Carboxypeptidase D (EC 3.4.17.22) (Metallocarboxypeptidase D) (gp180) CPD 1380 P55287 CAD11_HUMAN Cadherin-11 (OSF-4) (Osteoblast cadherin) (OB-cadherin) CDH11 796 P55291 CAD15_HUMAN Cadherin-15 (Cadherin-14) (Muscle cadherin) (M-cadherin) CDH15 CDH14 814 CDH3 O75309 CAD16_HUMAN Cadherin-16 (Kidney-specific cadherin) (Ksp-cadherin) CDH16 829 UNQ695/PRO1340 Q9H159 CAD19_HUMAN Cadherin-19 CDH19 CDH7L2 772 UNQ478/PRO941 P12830 CADH1_HUMAN Cadherin-1 (CAM 120/80) (Epithelial cadherin) (E-cadherin) (Uvomorulin) (CD antigen CDH1 CDHE UVO 882 CD324) [Cleaved into: E-Cad/CTF1; E-Cad/CTF2; E-Cad/CTF3] P22223 CADH3_HUMAN Cadherin-3 (Placental cadherin) (P-cadherin) CDH3 CDHP 829 Q9ULB4 CADH9_HUMAN Cadherin-9 CDH9 789 Q8N126 CADM3_HUMAN Cell adhesion molecule 3 (Brain immunoglobulin receptor) (Immunoglobulin superfamily CADM3 IGSF4B 398 member 4B) (IgSF4B) (Nectin-like protein 1) (NECL-1) (Synaptic cell adhesion molecule NECL1 SYNCAM3 3) (SynCAM3) (TSLC1-like protein 1) (TSLL1) TSLL1 UNQ225/PRO258 O43570 CAH12_HUMAN Carbonic anhydrase 12 (EC 4.2.1.1) (Carbonate dehydratase XII) (Carbonic anhydrase CA12 354 XII) (CA-XII) (Tumor antigen HOM-RCC-3.1.3) P15813 CD1D_HUMAN Antigen-presenting glycoprotein CD1d (R3G1) (CD antigen CD1d) CD1D 335 Q9BZW8 CD244_HUMAN Natural killer cell receptor 2B4 (NK cell activation-inducing ligand) (NAIL) (NK cell type I CD244 2B4 370 receptor protein 2B4) (NKR2B4) (h2B4) (SLAM family member 4) (SLAMF4) (Signaling lymphocytic activation molecule 4) (CD antigen CD244) Q5ZPR3 CD276_HUMAN CD276 antigen (4Ig-B7-H3) (B7 homolog 3) (B7-H3) (Costimulatory molecule) (CD CD276 B7H3 534 antigen CD276) PSEC0249 UNQ309/PRO352 P34810 CD68_HUMAN Macrosialin (Gp110) (CD antigen CD68) CD68 354 P40259 CD79B_HUMAN B-cell antigen receptor complex-associated protein beta chain (B-cell-specific CD79B B29 IGB 229 glycoprotein B29) (Ig-beta) (Immunoglobulin-associated B29 protein) (CD antigen CD79b) P01732 CD8A_HUMAN T-cell surface glycoprotein CD8 alpha chain (T-lymphocyte differentiation antigen T8/Leu- CD8A MAL 235 2) (CD antigen CD8a) P06126 CD1A_HUMAN T-cell surface glycoprotein CD1a (T-cell surface antigen T6/Leu-6) (hTa1 thymocyte CD1A 327 antigen) (CD antigen CD1a) P20273 CD22_HUMAN B-cell receptor CD22 (B-lymphocyte cell adhesion molecule) (BL-CAM) (Sialic acid- CD22 SIGLEC2 847 binding Ig-like lectin 2) (Siglec-2) (T-cell surface antigen Leu-14) (CD antigen CD22) P06127 CD5_HUMAN T-cell surface glycoprotein CD5 (Lymphocyte antigen T1/Leu-1) (CD antigen CD5) CD5 LEU1 495 P10966 CD8B_HUMAN T-cell surface glycoprotein CD8 beta chain (CD antigen CD8b) CD8B CD8B1 210 P14209 CD99_HUMAN CD99 antigen (12E7) (E2 antigen) (Protein MIC2) (T-cell surface glycoprotein E2) (CD CD99 MIC2 MIC2X 185 antigen CD99) MIC2Y P29017 CD1C_HUMAN T-cell surface glycoprotein CD1c (CD antigen CD1c) CD1C 333 P10747 CD28_HUMAN T-cell-specific surface glycoprotein CD28 (TP44) (CD antigen CD28) CD28 220 A6NJW9 CD8BL_HUMAN Putative T-cell surface glycoprotein CD8 beta-2 chain (CD8b pseudogene) CD8BP CD8B2 211 Q9BYE9 CDHR2_HUMAN Cadherin-related family member 2 (Protocadherin LKC) (PC-LKC) (Protocadherin-24) CDHR2 PCDH24 1310 PCLKC Q9HBB8 CDHR5_HUMAN Cadherin-related family member 5 (Mu-protocadherin) (Mucin and cadherin-like protein) CDHR5 MUCDHL 845 (Mucin-like protocadherin) (MLPCDH) MUPCDH UNQ2781/PRO7168 Q6UY09 CEA20_HUMAN Carcinoembryonic antigen-related cell adhesion molecule 20 CEACAM20 585 UNQ9366/PRO34155 Q3KPI0 CEA21_HUMAN Carcinoembryonic antigen-related cell adhesion molecule 21 CEACAM21 293 UNQ3098/PRO10075 P15391 CD19_HUMAN B-lymphocyte antigen CD19 (B-lymphocyte surface antigen B4) (Differentiation antigen CD19 556 CD19) (T-cell surface antigen Leu-12) (CD antigen CD19) P15812 CD1E_HUMAN T-cell surface glycoprotein CD1e, membrane-associated (hCD1e) (R2G1) (CD antigen CD1E 388 CD1e) [Cleaved into: T-cell surface glycoprotein CD1e, soluble (sCD1e)] Q15762 CD226_HUMAN CD226 antigen (DNAX accessory molecule 1) (DNAM-1) (CD antigen CD226) CD226 DNAM1 336 P26842 CD27_HUMAN CD27 antigen (CD27L receptor) (T-cell activation antigen CD27) (T14) (Tumor necrosis CD27 TNFRSF7 260 factor receptor superfamily member 7) (CD antigen CD27) P06729 CD2_HUMAN T-cell surface antigen CD2 (Erythrocyte receptor) (LFA-2) (LFA-3 receptor) (Rosette CD2 SRBC 351 receptor) (T-cell surface antigen T11/Leu-5) (CD antigen CD2) Q9NPF0 CD320_HUMAN CD320 antigen (8D6 antigen) (FDC-signaling molecule 8D6) (FDC-SM-8D6) CD320 8D6A 282 (Transcobalamin receptor) (TCbIR) (CD antigen CD320) UNQ198/PRO224 P04234 CD3D_HUMAN T-cell surface glycoprotein CD3 delta chain (T-cell receptor T3 delta chain) (CD antigen CD3D T3D 171 CD3d) P16070 CD44_HUMAN CD44 antigen (CDw44) (Epican) (Extracellular matrix receptor III) (ECMR-III) (GP90 CD44 LHR MDU2 742 lymphocyte homing/adhesion receptor) (HUTCH-I) (Heparan sulfate proteoglycan) MDU3 MIC4 (Hermes antigen) (Hyaluronate receptor) (Phagocytic glycoprotein 1) (PGP-1) (Phagocytic glycoprotein I) (PGP-I) (CD antigen CD44) P30203 CD6_HUMAN T-cell differentiation antigen CD6 (T12) (TP120) (CD antigen CD6) [Cleaved into: Soluble CD6 668 CD6] P33681 CD80_HUMAN T-lymphocyte activation antigen CD80 (Activation B7-1 antigen) (BB1) (CTLA-4 counter- CD80 CD28LG 288 receptor B7.1) (B7) (CD antigen CD80) CD28LG1 LAB7 P13688 CEAM1_HUMAN Carcinoembryonic antigen-related cell adhesion molecule 1 (Biliary glycoprotein 1) (BGP- CEACAM1 BGP 526 1) (CD antigen CD66a) BGP1 P29016 CD1B_HUMAN T-cell surface glycoprotein CD1b (CD antigen CD1b) CD1B 333 Q9HCU0 CD248_HUMAN Endosialin (Tumor endothelial marker 1) (CD antigen CD248) CD248 CD164L1 757 TEM1 P28906 CD34_HUMAN Hematopoietic progenitor cell antigen CD34 (CD antigen CD34) CD34 385 P07766 CD3E_HUMAN T-cell surface glycoprotein CD3 epsilon chain (T-cell surface antigen T3/Leu-4 epsilon CD3E T3E 207 chain) (CD antigen CD3e) P09693 CD3G_HUMAN T-cell surface glycoprotein CD3 gamma chain (T-cell receptor T3 gamma chain) (CD CD3G T3G 182 antigen CD3g) Q6ZTQ4 CDHR3_HUMAN Cadherin-related family member 3 (Cadherin-like protein 28) CDHR3 CDH28 885 P20963 CD3Z_HUMAN T-cell surface glycoprotein CD3 zeta chain (T-cell receptor T3 zeta chain) (CD antigen CD247 CD3Z T3Z 164 CD247) TCRZ P11912 CD79A_HUMAN B-cell antigen receptor complex-associated protein alpha chain (Ig-alpha) (MB-1 CD79A IGA MB1 226 membrane glycoprotein) (Membrane-bound immunoglobulin-associated protein) (Surface IgM-associated protein) (CD antigen CD79a) O75871 CEAM4_HUMAN Carcinoembryonic antigen-related cell adhesion molecule 4 (Carcinoembryonic antigen CEACAM4 CGM7 244 CGM7) (Non-specific cross-reacting antigen W236) Q13740 CD166_HUMAN CD166 antigen (Activated leukocyte cell adhesion molecule) (CD antigen CD166) ALCAM MEMD 583 Q99467 CD180_HUMAN CD180 antigen (Lymphocyte antigen 64) (Radioprotective 105 kDa protein) (CD antigen CD180 LY64 RP105 661 CD180) Q8IX05 CD302_HUMAN CD302 antigen (C-type lectin BIMLEC) (C-type lectin domain family 13 member A) CD302 CLEC13A 232 (DEC205-associated C-type lectin 1) (Type I transmembrane C-type lectin receptor DCL- DCL1KIAA0022 1) (CD antigen CD302) P20138 CD33_HUMAN Myeloid cell surface antigen CD33 (Sialic acid-binding Ig-like lectin 3) (Siglec-3) (gp67) CD33 SIGLEC3 364 (CD antigen CD33) P01730 CD4_HUMAN T-cell surface glycoprotein CD4 (T-cell surface antigen T4/Leu-3) (CD antigen CD4) CD4 458 P09564 CD7_HUMAN T-cell antigen CD7 (GP40) (T-cell leukemia antigen) (T-cell surface antigen Leu-9) (TP41) CD7 240 (CD antigen CD7) Q01151 CD83_HUMAN CD83 antigen (hCD83) (B-cell activation protein) (Cell surface protein HB15) (CD antigen CD83 205 CD83) P42081 CD86_HUMAN T-lymphocyte activation antigen CD86 (Activation B7-2 antigen) (B70) (BU63) (CTLA-4 CD86 CD28LG2 329 counter-receptor B7.2) (FUN-1) (CD antigen CD86) A6H8M9 CDHR4_HUMAN Cadherin-related family member 4 (Cadherin-like protein 29) CDHR4 CDH29 788 UNQ9392/PRO3430 0 Q7Z692 CEA19_HUMAN Carcinoembryonic antigen-related cell adhesion molecule 19 (Carcinoembryonic CEACAM19 CEAL1 300 antigen-like 1) UNQ2973/PRO7436 P40198 CEAM3_HUMAN Carcinoembryonic antigen-related cell adhesion molecule 3 (Carcinoembryonic CEACAM3 CD66D 252 antigen CGM1) (CD antigen CD66d) CGM1 Q9H9P2 CHODL_HUMAN Chondrolectin (Transmembrane protein MT75) CHODL C21orf68 273 PRED12 UNQ872/PRO1890 Q08708 CLM6_HUMAN CMRF35-like molecule 6 (CLM-6) (CD300 antigen-like family member C) (CMRF35-A1) CD300C CMRF35 224 (CMRF-35) (Immunoglobulin superfamily member 16) (IgSF16) (CD antigen CD300c) CMRF35A CMRF35A1 IGSF16 O14967 CLGN_HUMAN Calmegin CLGN 610 Q496F6 CLM2_HUMAN CMRF35-like molecule 2 (CLM-2) (CD300 antigen-like family member E) (CMRF35-A5) CD300E CD300LE 205 (Immune receptor expressed on myeloid cells 2) (IREM-2) (Polymeric immunoglobulin CLM2 CMRF35A5 receptor 2) (PIgR-2) (PIgR2) (Poly-Ig receptor 2) (CD antigen CD300e) IREM2 Q6UXG3 CLM9_HUMAN CMRF35-like molecule 9 (CLM-9) (CD300 antigen-like family member G) (Triggering CD300LG CLM9 332 receptor expressed on myeloid cells 4) (TREM-4) (CD antigen CD300g) TREM4 UNQ422/PRO846 Q9UQC9 CLCA2_HUMAN Calcium-activated chloride channel regulator 2 (EC 3.4.—.—) (Calcium-activated chloride CLCA2 CACC3 943 channel family member 2) (hCLCA2) (Calcium-activated chloride channel protein 3) (CaCC-3) (hCaCC-3) [Cleaved into: Calcium-activated chloride channel regulator 2, 109 kDa form; Calcium-activated chloride channel regulator 2, 35 kDa form] Q9H6B4 CLMP_HUMAN CXADR-like membrane protein (Adipocyte adhesion molecule) (Coxsackie- and CLMP ACAM ASAM 373 adenovirus receptor-like membrane protein) (CAR-like membrane protein) UNQ318/PRO363 Q96F05 CK024_HUMAN Uncharacterized protein C11orf24 (Protein DM4E3) C11orf24 FP2568 449 UNQ1872/PRO4315 Q6NUJ2 CK087_HUMAN Uncharacterized protein C11orf87 C11orf87 197 A8K4G0 CLM7_HUMAN CMRF35-like molecule 7 (CLM-7) (CD300 antigen-like family member B) (CMRF35-A2) CD300LB CD300B 201 (Immune receptor expressed on myeloid cells 3) (IREM-3) (Leukocyte mono-Ig-like CLM7 CMRF35A2 receptor 5) (Triggering receptor expressed on myeloid cells 5) (TREM-5) (CD antigen IREM3 LMIR5 CD300b) TREM5 UNQ2530/PRO6029 Q9UGN4 CLM8_HUMAN CMRF35-like molecule 8 (CLM-8) (CD300 antigen-like family member A) (CMRF-35-H9) CD300A CMRF35H 299 (CMRF35-H9) (CMRF35-H) (IRC1/IRC2) (Immunoglobulin superfamily member 12) IGSF12 HSPC083 (IgSF12) (Inhibitory receptor protein 60) (IRp60) (NK inhibitory receptor) (CD antigen CD300a) Q96NU0 CNT3B_HUMAN Contactin-associated protein-like 3B (Cell recognition molecule Caspr3b) CNTNAP3B 1288 CASPR3B P78357 CNTP1_HUMAN Contactin-associated protein 1 (Caspr) (Caspr1) (Neurexin IV) (Neurexin-4) (p190) CNTNAP1 CASPR 1384 NRXN4 Q9UHC6 CNTP2_HUMAN Contactin-associated protein-like 2 (Cell recognition molecule Caspr2) CNTNAP2 CASPR2 1331 KIAA0868 Q9C0A0 CNTP4_HUMAN Contactin-associated protein-like 4 (Cell recognition molecule Caspr4) CNTNAP4 CASPR4 1308 KIAA1763 Q8WYK1 CNTP5_HUMAN Contactin-associated protein-like 5 (Cell recognition molecule Caspr5) CNTNAP5 CASPR5 1306 Q8TDQ1 CLM1_HUMAN CMRF35-like molecule 1 (CLM-1) (CD300 antigen-like family member F) (Immune CD300LF CD300F 290 receptor expressed on myeloid cells 1) (IREM-1) (Immunoglobulin superfamily member CLM1 IGSF13 13) (IgSF13) (NK inhibitory receptor) (CD antigen CD300f) IREM1 NKIR UNQ3105/PRO10111 Q5T292 CJ128_HUMAN Putative uncharacterized protein C10orf128 C10orf128 105 Q86T13 CLC14_HUMAN C-type lectin domain family 14 member A (Epidermal growth factor receptor 5) (EGFR-5) CLEC14A C14orf27 490 EGFR5 UNQ236/PRO269 Q6UXZ3 CLM4_HUMAN CMRF35-like molecule 4 (CLM-4) (CD300 antigen-like family member D) (CMRF35-A4) CD300LD CD300D 194 (CD antigen CD300d) CMRF35A4 UNQ9218/PRO28686 Q9BZ76 CNTP3_HUMAN Contactin-associated protein-like 3 (Cell recognition molecule Caspr3) CNTNAP3 CASPR3 1288 KIAA1714 Q86TY3 CN037_HUMAN Uncharacterized protein C14orf37 C14orf37 774 Q9HC73 CRLF2_HUMAN Cytokine receptor-like factor 2 (Cytokine receptor-like 2) (IL-XR) (Thymic stromal CRLF2 CRL2 ILXR 371 lymphopoietin protein receptor) (TSLP receptor) TSLPR Q9BVV8 CS024_HUMAN Uncharacterized membrane protein C19orf24 C19orf24 132 P09603 CSF1_HUMAN Macrophage colony-stimulating factor 1 (CSF-1) (M-CSF) (MCSF) (Lanimostim) [Cleaved CSF1 554 into: Processed macrophage colony-stimulating factor 1] Q5IJ48 CRUM2_HUMAN Protein crumbs homolog 2 (Crumbs-like protein 2) CRB2 1285 Q96PZ7 CSMD1_HUMAN CUB and sushi domain-containing protein 1 (CUB and sushi multiple domains protein 1) CSMD1 KIAA1890 3565 UNQ5952/PRO19863 O95196 CSPG5_HUMAN Chondroitin sulfate proteoglycan 5 (Acidic leucine-rich EGF-like domain-containing brain CSPG5 CALEB 566 protein) (Neuroglycan C) NGC Q9BUF7 CRUM3_HUMAN Protein crumbs homolog 3 CRB3 120 UNQ588/PRO1158 O94985 CSTN1_HUMAN Calsyntenin-1 (Alcadein-alpha) (Alc-alpha) (Alzheimer-related cadherin-like protein) (Non- CLSTN1 CS1 981 classical cadherin XB31alpha) [Cleaved into: Soluble Alc-alpha (SAlc-alpha); CTF1-alpha KIAA0911 (C-terminal fragment 1-alpha)] Q6ZRH7 CTSRG_HUMAN Cation channel sperm-associated protein subunit gamma CATSPERG 1159 C19orf15 Q86UP6 CUZD1_HUMAN CUB and zona pellucida-like domain-containing protein 1 (CUB and ZP domain- CUZD1 607 containing protein 1) (Transmembrane protein UO-44) UNQ224/PRO257 Q5JRM2 CX066_HUMAN Uncharacterized protein CXorf66 CXorf66 361 Q8NEA5 CS018_HUMAN Uncharacterized protein C19orf18 C19orf18 215 P17927 CR1_HUMAN Complement receptor type 1 (C3b/C4b receptor) (CD antigen CD35) CR1 C3BR 2039 P20023 CR2_HUMAN Complement receptor type 2 (Cr2) (Complement C3d receptor) (Epstein-Barr virus CR2 C3DR 1033 receptor) (EBV receptor) (CD antigen CD21) P15509 CSF2R_HUMAN Granulocyte-macrophage colony-stimulating factor receptor subunit alpha (GM-CSF-R- CSF2RA CSF2R 400 alpha) (GMCSFR-alpha) (GMR-alpha) (CDw116) (CD antigen CD116) CSF2RY Q99062 CSF3R_HUMAN Granulocyte colony-stimulating factor receptor (G-CSF receptor) (G-CSF-R) (CD antigen CSF3R GCSFR 836 CD114) Q9BQT9 CSTN3_HUMAN Calsyntenin-3 (Alcadein-beta) (Alc-beta) CLSTN3 CS3 956 KIAA0726 Q9NZV1 CRIM1_HUMAN Cysteine-rich motor neuron 1 protein (CRIM-1) (Cysteine-rich repeat-containing protein CRIM1 S52 1036 S52) [Cleaved into: Processed cysteine-rich motor neuron 1 protein] UNQ1886/PRO4330 P82279 CRUM1_HUMAN Protein crumbs homolog 1 CRB1 1406 Q6UVK1 CSPG4_HUMAN Chondroitin sulfate proteoglycan 4 (Chondroitin sulfate proteoglycan NG2) (Melanoma CSPG4 MCSP 2322 chondroitin sulfate proteoglycan) (Melanoma-associated Chondroitin sulfate proteoglycan) P16410 CTLA4_HUMAN Cytotoxic T-lymphocyte protein 4 (Cytotoxic T-lymphocyte-associated antigen 4) (CTLA- CTLA4 CD152 223 4) (CD antigen CD152) Q86XM0 CTSRD_HUMAN Cation channel sperm-associated protein subunit delta (CatSper-delta) (CatSperdelta) CATSPERD 798 (Transmembrane protein 146) TMEM146 P78310 CXAR_HUMAN Coxsackievirus and adenovirus receptor (CAR) (hCAR) (CVB3-binding protein) CXADR CAR 365 (Coxsackievirus B-adenovirus receptor) (HCVADR) O95727 CRTAM_HUMAN Cytotoxic and regulatory T-cell molecule (Class-I MHC-restricted T-cell-associated CRTAM 393 molecule) (CD antigen CD355) P07333 CSF1R_HUMAN Macrophage colony-stimulating factor 1 receptor (CSF-1 receptor) (CSF-1-R) (CSF-1R) CSF1R FMS 972 (M-CSF-R) (EC 2.7.10.1) (Proto-oncogene c-Fms) (CD antigen CD115) Q4G0I0 CSMT1_HUMAN Protein CCSMST1 CCSMST1 132 C16orf91 Q9H4D0 CSTN2_HUMAN Calsyntenin-2 (Alcadein-gamma) (Alc-gamma) CLSTN2 CS2 955 Q9H2A7 CXL16_HUMAN C-X-C motif chemokine 16 (Scavenger receptor for phosphatidylserine and oxidized low CXCL16 SCYB16 254 density lipoprotein) (SR-PSOX) (Small-inducible cytokine B16) (Transmembrane SRPSOX chemokine CXCL16) UNQ2759/PRO6714 P08174 DAF_HUMAN Complement decay-accelerating factor (CD antigen CD55) CD55 CR DAF 381 Q14118 DAG1_HUMAN Dystroglycan (Dystrophin-associated glycoprotein 1) [Cleaved into: Alpha-dystroglycan DAG1 895 (Alpha-DG); Beta-dystroglycan (Beta-DG)] Q96J86 CYYR1_HUMAN Cysteine and tyrosine-rich protein 1 (Proline-rich domain-containing protein) CYYR1 C21orf95 154 P43146 DCC_HUMAN Netrin receptor DCC (Colorectal cancer suppressor) (Immunoglobulin superfamily DCC DCC IGDCC1 1447 subclass member 1) (Tumor suppressor protein DCC) Q08345 DDR1_HUMAN Epithelial discoidin domain-containing receptor 1 (Epithelial discoidin domain receptor 1) DDR1 CAK EDDR1 913 (EC 2.7.10.1) (CD167 antigen-like family member A) (Cell adhesion kinase) (Discoidin NEP NTRK4 PTK3A receptor tyrosine kinase) (HGK2) (Mammary carcinoma kinase 10) (MCK-10) (Protein- RTK6 TRKE tyrosine kinase 3A) (Protein-tyrosine kinase RTK-6) (TRK E) (Tyrosine kinase DDR) (Tyrosine-protein kinase CAK) (CD antigen CD167a) Q16832 DDR2_HUMAN Discoidin domain-containing receptor 2 (Discoidin domain receptor 2) (EC 2.7.10.1) DDR2 NTRKR3 855 (CD167 antigen-like family member B) (Discoidin domain-containing receptor tyrosine TKT TYRO10 kinase 2) (Neurotrophic tyrosine kinase, receptor-related 3) (Receptor protein-tyrosine kinase TKT) (Tyrosine-protein kinase TYRO10) (CD antigen CD167b) Q8N8Z6 DCBD1_HUMAN Discoidin, CUB and LCCL domain-containing protein 1 DCBLD1 715 Q96PD2 DCBD2_HUMAN Discoidin, CUB and LCCL domain-containing protein 2 (CUB, LCCL and coagulation DCBLD2 CLCP1 775 factor V/VIII-homology domains protein 1) (Endothelial and smooth muscle cell-derived ESDN neuropilin-like protein) P28068 DMB_HUMAN HLA class II histocompatibility antigen, DM beta chain (MHC class II antigen DMB) HLA-DMB DMB 263 (Really interesting new gene 7 protein) RING7 P80370 DLK1_HUMAN Protein delta homolog 1 (DLK-1) (pG2) [Cleaved into: Fetal antigen 1 (FA1)] DLK1 DLK 383 Q9NYJ7 DLL3_HUMAN Delta-like protein 3 (Drosophila Delta homolog 3) (Delta3) DLL3 618 P28067 DMA_HUMAN HLA class II histocompatibility antigen, DM alpha chain (MHC class II antigen DMA) HLA-DMA DMA 261 (Really interesting new gene 6 protein) RING6 P06340 DOA_HUMAN HLA class II histocompatibility antigen, DO alpha chain (MHC DN-alpha) (MHC DZ alpha) HLA-DOA HLA-DNA 250 (MHC class II antigen DOA) HLA-DZA Q6UY11 DLK2_HUMAN Protein delta homolog 2 (DLK-2) (Epidermal growth factor-like protein 9) (EGF-like protein DLK2 EGFL9 383 9) UNQ2903/PRO28633 Q8NFT8 DNER_HUMAN Delta and Notch-like epidermal growth factor-related receptor DNER BET 737 UNQ262/PRO299 P20036 DPA1_HUMAN HLA class II histocompatibility antigen, DP alpha 1 chain (DP(W3)) (DP(W4)) (HLA-SB HLA-DPA1 HLA- 260 alpha chain) (MHC class II DP3-alpha) (MHC class II DPA1) DP1A HLASB P79483 DRB3_HUMAN HLA class II histocompatibility antigen, DR beta 3 chain (MHC class II antigen DRB3) HLA-DRB3 266 Q96KC8 DNJC1_HUMAN DnaJ homolog subfamily C member 1 (DnaJ protein homolog MTJ1) DNAJC1 HTJ1 554 Q8TD84 DSCL1_HUMAN Down syndrome cell adhesion molecule-like protein 1 (Down syndrome cell adhesion DSCAML1 2053 molecule 2) DSCAM2 KIAA1132 O00548 DLL1_HUMAN Delta-like protein 1 (Drosophila Delta homolog 1) (Delta1) (H-Delta-1) DLL1 723 UNQ146/PRO172 Q02487 DSC2_HUMAN Desmocollin-2 (Cadherin family member 2) (Desmocollin-3) (Desmosomal glycoprotein II) DSC2 CDHF2 901 (Desmosomal glycoprotein III) DSC3 O60469 DSCAM_HUMAN Down syndrome cell adhesion molecule (CHD2) DSCAM 2012 Q9NR61 DLL4_HUMAN Delta-like protein 4 (Drosophila Delta homolog 4) (Delta4) DLL4 685 UNQ1895/PRO4341 P13765 DOB_HUMAN HLA class II histocompatibility antigen, DO beta chain (MHC class II antigen DOB) HLA-DOB 273 P01906 DQA2_HUMAN HLA class II histocompatibility antigen, DQ alpha 2 chain (DX alpha chain) (HLA class II HLA-DQA2 HLA- 255 histocompatibility antigen, DQ(6) alpha chain) (HLA-DQA1) (MHC class II DQA2) DXA P01920 DQB1_HUMAN HLA class II histocompatibility antigen, DQ beta 1 chain (MHC class II antigen DQB1) HLA-DQB1 HLA- 261 DQB Q30154 DRB5_HUMAN HLA class II histocompatibility antigen, DR beta 5 chain (DR beta-5) (DR2-beta-2) (Dw2) HLA-DRB5 266 (MHC class II antigen DRB5) Q14574 DSC3_HUMAN Desmocollin-3 (Cadherin family member 3) (Desmocollin-4) (HT-CP) DSC3 CDHF3 896 DSC4 P01909 DQA1_HUMAN HLA class II histocompatibility antigen, DQ alpha 1 chain (DC-1 alpha chain) (DC-alpha) HLA-DQA1 254 (HLA-DCA) (MHC class II DQA1) P32926 DSG3_HUMAN Desmoglein-3 (130 kDa pemphigus vulgaris antigen) (PVA) (Cadherin family member 6) DSG3 CDHF6 999 Q9NZJ5 E2AK3_HUMAN Eukaryotic translation initiation factor 2-alpha kinase 3 (EC 2.7.11.1) (PRKR-like EIF2AK3 PEK 1116 endoplasmic reticulum kinase) (Pancreatic eIF2-alpha kinase) (HsPEK) PERK P04440 DPB1_HUMAN HLA class II histocompatibility antigen, DP beta 1 chain (HLA class II histocompatibility HLA-DPB1 HLA- 258 antigen, DP(W4) beta chain) (MHC class II antigen DPB1) DP1B P13762 DRB4_HUMAN HLA class II histocompatibility antigen, DR beta 4 chain (MHC class II antigen DRB4) HLA-DRB4 266 Q86SJ6 DSG4_HUMAN Desmoglein-4 (Cadherin family member 13) DSG4 CDHF13 1040 Q3MIW9 DPCR1_HUMAN Diffuse panbronchiolitis critical region protein 1 DPCR1 C6orf37 517 PBLT P01903 DRA_HUMAN HLA class II histocompatibility antigen, DR alpha chain (MHC class II antigen DRA) HLA-DRA HLA- 254 DRA1 Q08554 DSC1_HUMAN Desmocollin-1 (Cadherin family member 1) (Desmosomal glycoprotein 2/3) (DG2/DG3) DSC1 CDHF1 894 Q02413 DSG1_HUMAN Desmoglein-1 (Cadherin family member 4) (Desmosomal glycoprotein 1) (DG1) (DGI) DSG1 CDHF4 1049 (Pemphigus foliaceus antigen) P05538 DQB2_HUMAN HLA class II histocompatibility antigen, DQ beta 2 chain (HLA class II histocompatibility HLA-DQB2 HLA- 268 antigen, DX beta chain) (MHC class II antigen DQB2) DXB Q14126 DSG2_HUMAN Desmoglein-2 (Cadherin family member 5) (HDGC) DSG2 CDHF5 1118 P01133 EGF_HUMAN Pro-epidermal growth factor (EGF) [Cleaved into: Epidermal growth factor (Urogastrone)] EGF 1207 Q19T08 ECSCR_HUMAN Endothelial cell-specific chemotaxis regulator (Apoptosis regulator through modulating ECSCR ECSM2 205 IAP expression) (ARIA) (Endothelial cell-specific molecule 2) Q9UNE0 EDAR_HUMAN Tumor necrosis factor receptor superfamily member EDAR (Anhidrotic ectodysplasin EDAR DL 448 receptor 1) (Downless homolog) (EDA-A1 receptor) (Ectodermal dysplasia receptor) (Ectodysplasin-A receptor) P98172 EFNB1_HUMAN Ephrin-B1 (EFL-3) (ELK ligand) (ELK-L) (EPH-related receptor tyrosine kinase ligand 2) EFNB1 EFL3 346 (LERK-2) EPLG2 LERK2 Q15768 EFNB3_HUMAN Ephrin-B3 (EPH-related receptor transmembrane ligand ELK-L3) (EPH-related receptor EFNB3 EPLG8 340 tyrosine kinase ligand 8) (LERK-8) LERK8 Q9NPA0 EMC7_HUMAN ER membrane protein complex subunit 7 EMC7 C11orf3 242 C15orf24 HT022 UNQ905/PRO1926 Q902F9 EN113_HUMAN Endogenous retrovirus group K member 113 Env polyprotein (EnvK5 protein) (Envelope HERVK_113 699 polyprotein) (HERV-K113 envelope protein) (HERV-K_19p13.11 provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] Q6UWV6 ENPP7_HUMAN Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (E-NPP 7) (NPP-7) ENPP7 458 (EC 3.1.4.12) (Alkaline sphingomyelin phosphodiesterase) (Intestinal alkaline UNQ3077/PRO9912 sphingomyelinase) (Alk-SMase) P61566 ENK24_HUMAN Endogenous retrovirus group K member 24 Env polyprotein (Envelope polyprotein) ERVK-24 588 (HERV-K101 envelope protein) (HERV-K_22q11.21 provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] Q902F8 ENK8_HUMAN Endogenous retrovirus group K member 8 Env polyprotein (EnvK6 protein) (Envelope ERVK-8 699 polyprotein) (HERV-K115 envelope protein) (HERV-K_8p23.1 provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] P29320 EPHA3_HUMAN Ephrin type-A receptor 3 (EC 2.7.10.1) (EPH-like kinase 4) (EK4) (hEK4) (HEK) (Human EPHA3 ETK ETK1 983 embryo kinase) (Tyrosine-protein kinase TYRO4) (Tyrosine-protein kinase receptor HEK TYRO4 ETK1) (Eph-like tyrosine kinase 1) P54764 EPHA4_HUMAN Ephrin type-A receptor 4 (EC 2.7.10.1) (EPH-like kinase 8) (EK8) (hEK8) (Tyrosine- EPHA4 HEK8 SEK 986 protein kinase TYRO1) (Tyrosine-protein kinase receptor SEK) TYRO1 Q9UF33 EPHA6_HUMAN Ephrin type-A receptor 6 (EC 2.7.10.1) (EPH homology kinase 2) (EHK-2) (EPH-like EPHA6 EHK2 1036 kinase 12) (EK12) HEK12 Q5JZY3 EPHAA_HUMAN Ephrin type-A receptor 10 (EC 2.7.10.1) EPHA10 1008 P19235 EPOR_HUMAN Erythropoietin receptor (EPO-R) EPOR 508 P04626 ERBB2_HUMAN Receptor tyrosine-protein kinase erbB-2 (EC 2.7.10.1) (Metastatic lymph node gene 19 ERBB2 HER2 1255 protein) (MLN 19) (Proto-oncogene Neu) (Proto-oncogene c-ErbB-2) (Tyrosine kinase- MLN19 NEU NGL type cell surface receptor HER2) (p185erbB2) (CD antigen CD340) P52799 EFNB2_HUMAN Ephrin-B2 (EPH-related receptor tyrosine kinase ligand 5) (LERK-5) (HTK ligand) (HTK-L) EFNB2 EPLG5 333 HTKL LERK5 P17813 EGLN_HUMAN Endoglin (CD antigen CD105) ENG END 658 Q5UCC4 EMC10_HUMAN ER membrane protein complex subunit 10 (Hematopoietic signal peptide-containing EMC10 C19orf63 262 membrane domain-containing protein 1) HSM1 INM02 UNQ764/PRO1556 Q69384 ENK6_HUMAN Endogenous retrovirus group K member 6 Env polyprotein (EnvK2 protein) (Envelope ERVK-6 ERVK6 699 polyprotein) (HERV-K(C7) envelope protein) (HERV-K(HML-2.HOM) envelope protein) (HERV-K108 envelope protein) (HERV-K_7p22.1 provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] Q9UKH3 ENK9_HUMAN Endogenous retrovirus group K member 9 Env polyprotein (EnvK4 protein) (Envelope ERVK-9 698 polyprotein) (HERV-K(C6) envelope protein) (HERV-K109 envelope protein) (HERV- K_6q14.1 provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] Q6UW88 EPGN_HUMAN Epigen (Epithelial mitogen) (EPG) EPGN 154 UNQ3072/PRO9904 P29317 EPHA2_HUMAN Ephrin type-A receptor 2 (EC 2.7.10.1) (Epithelial cell kinase) (Tyrosine-protein kinase EPHA2 ECK 976 receptor ECK) P54753 EPHB3_HUMAN Ephrin type-B receptor 3 (EC 2.7.10.1) (EPH-like tyrosine kinase 2) (EPH-like kinase 2) EPHB3 ETK2 HEK2 998 (Embryonic kinase 2) (EK2) (hEK2) (Tyrosine-protein kinase TYRO6) TYRO6 O15197 EPHB6_HUMAN Ephrin type-B receptor 6 (HEP) (Tyrosine-protein kinase-defective receptor EPH-6) EPHB6 1021 O14944 EREG_HUMAN Proepiregulin [Cleaved into: Epiregulin (EPR)] EREG 169 B6SEH8 ERVV1_HUMAN Endogenous retrovirus group V member 1 Env polyprotein (HERV-V_19q13.41 provirus ERVV-1 ENVV1 477 ancestral Env polyprotein 1) P00533 EGFR_HUMAN Epidermal growth factor receptor (EC 2.7.10.1) (Proto-oncogene c-ErbB-1) (Receptor EGFR ERBB 1210 tyrosine-protein kinase erbB-1) ERBB1 HER1 Q8N766 EMC1_HUMAN ER membrane protein complex subunit 1 EMC1 KIAA0090 993 PSEC0263 O42043 ENK18_HUMAN Endogenous retrovirus group K member 18 Env polyprotein (Envelope polyprotein) ERVK-18 560 (HERV-K(C1a) envelope protein) (HERV-K110 envelope protein) (HERV-K18 envelope protein) (HERV-K18 superantigen) (HERV-K_1q23.3 provirus ancestral Env polyprotein) (IDDMK1, 2 22 envelope protein) (IDDMK1, 2 22 superantigen) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] O71037 ENK19_HUMAN Endogenous retrovirus group K member 19 Env polyprotein (EnvK3 protein) (Envelope ERVK-19 699 polyprotein) (HERV-K(C19) envelope protein) (HERV-K_19q11 provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] Q15375 EPHA7_HUMAN Ephrin type-A receptor 7 (EC 2.7.10.1) (EPH homology kinase 3) (EHK-3) (EPH-like EPHA7 EHK3 998 kinase 11) (EK11) (hEK11) HEK11 Q9NQ60 EQTN_HUMAN Equatorin (Acrosome formation-associated factor) EQTN AFAF 294 C9orf11 P61565 ENK21_HUMAN Endogenous retrovirus group K member 21 Env polyprotein (EnvK1 protein) (Envelope ERVK-21 698 polyprotein) (HERV-K_12q14.1 provirus ancestral Env polyprotein) [Cleaved into: Surface protein (SU); Transmembrane protein (TM)] Q9UNN8 EPCR_HUMAN Endothelial protein C receptor (Activated protein C receptor) (APC receptor) (Endothelial PROCR EPCR 238 cell protein C receptor) (CD antigen CD201) P54762 EPHB1_HUMAN Ephrin type-B receptor 1 (EC 2.7.10.1) (ELK) (EPH tyrosine kinase 2) (EPH-like kinase 6) EPHB1 ELK EPHT2 984 (EK6) (hEK6) (Neuronally-expressed EPH-related tyrosine kinase) (NET) (Tyrosine- HEK6 NET protein kinase receptor EPH-2) P54760 EPHB4_HUMAN Ephrin type-B receptor 4 (EC 2.7.10.1) (Hepatoma transmembrane kinase) (Tyrosine- EPHB4 HTK MYK1 987 protein kinase TYRO11) TYRO11 P21860 ERBB3_HUMAN Receptor tyrosine-protein kinase erbB-3 (EC 2.7.10.1) (Proto-oncogene-like protein c- ERBB3 HER3 1342 ErbB-3) (Tyrosine kinase-type cell surface receptor HER3) A8MVW0 F1712_HUMAN Protein FAM171A2 FAM171A2 826 Q5JX69 F209B_HUMAN Protein FAM209B FAM209B 171 C20orf107 P0C7U0 ELFN1_HUMAN Protein ELFN1 (Extracellular leucine-rich repeat and fibronectin type-III domain- ELFN1 PPP1R28 828 containing protein 1) (Protein phosphatase 1 regulatory subunit 28) Q6PCB8 EMB_HUMAN Embigin EMB 327 Q9Y6X5 ENPP4_HUMAN Bis(5′-adenosyl)-triphosphatase ENPP4 (EC 3.6.1.29) (AP3A hydrolase) (AP3Aase) ENPP4 KIAA0879 453 (Ectonucleotide pyrophosphatase/phosphodiesterase family member 4) (E-NPP 4) (NPP- NPP4 4) P21709 EPHA1_HUMAN Ephrin type-A receptor 1 (hEpha1) (EC 2.7.10.1) (EPH tyrosine kinase) (EPH tyrosine EPHA1 EPH EPHT 976 kinase 1) (Erythropoietin-producing hepatoma receptor) (Tyrosine-protein kinase receptor EPHT1 EPH) P54756 EPHA5_HUMAN Ephrin type-A receptor 5 (EC 2.7.10.1) (Brain-specific kinase) (EPH homology kinase 1) EPHA5 BSK EHK1 1037 (EHK-1) (EPH-like kinase 7) (EK7) (hEK7) HEK7 TYRO4 P29322 EPHA8_HUMAN Ephrin type-A receptor 8 (EC 2.7.10.1) (EPH- and ELK-related kinase) (EPH-like kinase EPHA8 EEK HEK3 1005 3) (EK3) (hEK3) (Tyrosine-protein kinase receptor EEK) KIAA1459 P29323 EPHB2_HUMAN Ephrin type-B receptor 2 (EC 2.7.10.1) (Developmentally-regulated Eph-related tyrosine EPHB2 DRT EPHT3 1055 kinase) (ELK-related tyrosine kinase) (EPH tyrosine kinase 3) (EPH-like kinase 5) (EK5) EPTH3 ERK HEK5 (hEK5) (Renal carcinoma antigen NY-REN-47) (Tyrosine-protein kinase TYRO5) TYRO5 (Tyrosine-protein kinase receptor EPH-3) P03372 ESR1_HUMAN Estrogen receptor (ER) (ER-alpha) (Estradiol receptor) (Nuclear receptor subfamily 3 ESR1 ESR NR3A1 595 group A member 1) Q15884 F1892_HUMAN Protein FAM189A2 (Protein X123) FAM189A2 C9orf61 450 X123 P16422 EPCAM_HUMAN Epithelial cell adhesion molecule (Ep-CAM) (Adenocarcinoma-associated antigen) (Cell EPCAM GA733-2 314 surface glycoprotein Trop-1) (Epithelial cell surface antigen) (Epithelial glycoprotein) M1S2 M4S1 MIC18 (EGP) (Epithelial glycoprotein 314) (EGP314) (hEGP314) (KS 1/4 antigen) (KSA) (Major TACSTD1 TROP1 gastrointestinal tumor-associated protein GA733-2) (Tumor-associated calcium signal transducer 1) (CD antigen CD326) Q15303 ERBB4_HUMAN Receptor tyrosine-protein kinase erbB-4 (EC 2.7.10.1) (Proto-oncogene-like protein c- ERBB4 HER4 1308 ErbB-4) (Tyrosine kinase-type cell surface receptor HER4) (p180erbB4) [Cleaved into: ERBB4 intracellular domain (4ICD) (E4ICD) (s80HER4)] O75460 ERN1_HUMAN Serine/threonine-protein kinase/endoribonuclease IRE1 (Endoplasmic reticulum-to- ERN1 IRE1 977 nucleus signaling 1) (Inositol-requiring protein 1) (hIRE1p) (Ire1-alpha) (IRE1a) [Includes: Serine/threonine-protein kinase (EC 2.7.11.1); Endoribonuclease (EC 3.1.26.—)] P58658 EVA1C_HUMAN Protein eva-1 homolog C (Protein FAM176C) (SUE21) EVA1C C21orf63 441 C21orf64 FAM176C PRED34 UNQ2504/PRO5993 P22794 EVI2A_HUMAN Protein EVI2A (Ecotropic viral integration site 2A protein homolog) (EVI-2A) EVI2A EVDA EVI2 236 Q5VUB5 F1711_HUMAN Protein FAM171A1 (Astroprincin) FAM171A1 890 C10orf38 Q6V0I7 FAT4_HUMAN Protocadherin Fat 4 (hFat4) (Cadherin family member 14) (FAT tumor suppressor FAT4 CDHF14 4981 homolog 4) (Fat-like cadherin protein FAT-J) FATJ Nbla00548 Q96PL5 ERMAP_HUMAN Erythroid membrane-associated protein (hERMAP) (Radin blood group antigen) (Scianna ERMAP RD SC 475 blood group antigen) Q76MJ5 ERN2_HUMAN Serine/threonine-protein kinase/endoribonuclease IRE2 (Endoplasmic reticulum-to- ERN2 IRE2 926 nucleus signaling 2) (Inositol-requiring protein 2) (hIRE2p) (Ire1-beta) (IRE1b) [Includes: Serine/threonine-protein kinase (EC 2.7.11.1); Endoribonuclease (EC 3.1.26.—)] Q96AP7 ESAM_HUMAN Endothelial cell-selective adhesion molecule ESAM 390 UNQ220/PRO246 P34910 EVI2B_HUMAN Protein EVI2B (Ecotropic viral integration site 2B protein homolog) (EVI-2B) (CD antigen EVI2B EVDB 448 CD361) Q3ZCQ3 F174B_HUMAN Membrane protein FAM174B FAM174B 159 Q8WWV6 FCAMR_HUMAN High affinity immunoglobulin alpha and immunoglobulin mu Fc receptor (Fc alpha/mu FCAMR FKSG87 532 receptor) (CD antigen CD351) P30273 FCERG_HUMAN High affinity immunoglobulin epsilon receptor subunit gamma (Fc receptor gamma-chain) FCER1G 86 (FcRgamma) (Fc-epsilon RI-gamma) (IgE Fc receptor subunit gamma) (FceRI gamma) Q8TBP5 F174A_HUMAN Membrane protein FAM174A (Hepatitis C virus NS5A-transactivated protein 6) (HCV FAM174A 190 NS5A-transactivated protein 6) (Transmembrane protein 157) NS5ATP6 TMEM157 UNQ1912/PRO4371 P31995 FCG2C_HUMAN Low affinity immunoglobulin gamma Fc region receptor II-c (IgG Fc receptor II-c) FCGR2C CD32 323 (CDw32) (Fc-gamma RII-c) (Fc-gamma-RIIc) (FcRII-c) (CD antigen CD32) FCG2 IGFR2 P55899 FCGRN_HUMAN IgG receptor FcRn large subunit p51 (FcRn) (IgG Fc fragment receptor transporter alpha FCGRT FCRN 365 chain) (Neonatal Fc receptor) Q96LA5 FCRL2_HUMAN Fc receptor-like protein 2 (FcR-like protein 2) (FcRL2) (Fc receptor homolog 2) (FcRH2) FCRL2 FCRH2 508 (IFGP family protein 4) (Immunoglobulin receptor translocation-associated protein 4) IFGP4 IRTA4 (SH2 domain-containing phosphatase anchor protein 1) (CD antigen CD307b) SPAP1 UNQ9236/PRO31998 Q96RD9 FCRL5_HUMAN Fc receptor-like protein 5 (FcR-like protein 5) (FcRL5) (BXMAS1) (Fc receptor homolog 5) FCRL5 FCRH5 977 (FcRH5) (Immune receptor translocation-associated protein 2) (CD antigen CD307e) IRTA2 UNQ503/PRO820 P31994 FCG2B_HUMAN Low affinity immunoglobulin gamma Fc region receptor II-b (IgG Fc receptor II-b) FCGR2B CD32 310 (CDw32) (Fc-gamma RII-b) (Fc-gamma-RIIb) (FcRII-b) (CD antigen CD32) FCG2 IGFR2 Q96PJ5 FCRL4_HUMAN Fc receptor-like protein 4 (FcR-like protein 4) (FcRL4) (Fc receptor homolog 4) (FcRH4) FCRL4 FCRH4 515 (IFGP family protein 2) (hIFGP2) (Immune receptor translocation-associated protein 1) IFGP2 IRTA1 (CD antigen CD307d) P22607 FGFR3_HUMAN Fibroblast growth factor receptor 3 (FGFR-3) (EC 2.7.10.1) (CD antigen CD333) FGFR3 JTK4 806 Q6P995 F171B_HUMAN Protein FAM171B FAM171B 826 KIAA1946 NPD019 A6NFU0 F187A_HUMAN Ig-like V-type domain-containing protein FAM187A FAM187A 413 Q17R55 F187B_HUMAN Protein FAM187B (Transmembrane protein 162) FAM187B 369 TMEM162 Q5JX71 F209A_HUMAN Protein FAM209A FAM209A 171 C20orf106 Q14517 FAT1_HUMAN Protocadherin Fat 1 (Cadherin family member 7) (Cadherin-related tumor suppressor FAT1 CDHF7 FAT 4588 homolog) (Protein fat homolog) [Cleaved into: Protocadherin Fat 1, nuclear form] Q9NYQ8 FAT2_HUMAN Protocadherin Fat 2 (hFat2) (Cadherin family member 8) (Multiple epidermal growth FAT2 CDHF8 4349 factor-like domains protein 1) (Multiple EGF-like domains protein 1) KIAA0811 MEGF1 Q8TDW7 FAT3_HUMAN Protocadherin Fat 3 (hFat3) (Cadherin family member 15) (FAT tumor suppressor FAT3 CDHF15 4589 homolog 3) KIAA1989 P24071 FCAR_HUMAN Immunoglobulin alpha Fc receptor (IgA Fc receptor) (CD antigen CD89) FCAR CD89 287 P12314 FCGR1_HUMAN High affinity immunoglobulin gamma Fc receptor I (IgG Fc receptor I) (Fc-gamma RI) FCGR1A FCG1 374 (FcRI) (Fc-gamma RIA) (FcgammaRIa) (CD antigen CD64) FCGR1 IGFR1 Q96LA6 FCRL1_HUMAN Fc receptor-like protein 1 (FcR-like protein 1) (FcRL1) (Fc receptor homolog 1) (FcRH1) FCRL1 FCRH1 429 (IFGP family protein 1) (hIFGP1) (Immune receptor translocation-associated protein 5) IFGP1 IRTA5 (CD antigen CD307a) Q96P31 FCRL3_HUMAN Fc receptor-like protein 3 (FcR-like protein 3) (FcRL3) (Fc receptor homolog 3) (FcRH3) FCRL3 FCRH3 734 (IFGP family protein 3) (hIFGP3) (Immune receptor translocation-associated protein 3) IFGP3 IRTA3 (SH2 domain-containing phosphatase anchor protein 2) (CD antigen CD307c) SPAP2 P12318 FCG2A_HUMAN Low affinity immunoglobulin gamma Fc region receptor II-a (IgG Fc receptor II-a) FCGR2A CD32 317 (CDw32) (Fc-gamma RII-a) (Fc-gamma-RIIa) (FcRII-a) (CD antigen CD32) FCG2 FCGR2A1 IGFR2 P08637 FCG3A_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-A (CD16a antigen) (Fc-gamma FCGR3A CD16A 254 RIII-alpha) (Fc-gamma RIII) (Fc-gamma RIIIa) (FcRIII) (FcRIIIa) (FcR-10) (IgG Fc FCG3 FCGR3 receptor III-2) (CD antigen CD16a) IGFR3 Q92637 FCGRB_HUMAN High affinity immunoglobulin gamma Fc receptor IB (IgG Fc receptor IB) (Fc-gamma RIB) FCGR1B IGFRB 280 (FcRIB) (hFcgammaRIB) Q8N441 FGRL1_HUMAN Fibroblast growth factor receptor-like 1 (FGF receptor-like protein 1) (FGF homologous FGFRL1 FGFR5 504 factor receptor) (FGFR-like protein) (Fibroblast growth factor receptor 5) (FGFR-5) FHFR UNQ480/PRO943 P12319 FCERA_HUMAN High affinity immunoglobulin epsilon receptor subunit alpha (Fc-epsilon RI-alpha) (FcERI) FCER1A FCE1A 257 (IgE Fc receptor subunit alpha) Q6DN72 FCRL6_HUMAN Fc receptor-like protein 6 (FcR-like protein 6) (FcRL6) (Fc receptor homolog 6) (FcRH6) FCRL6 FCRH6 434 (IFGP6) P11362 FGFR1_HUMAN Fibroblast growth factor receptor 1 (FGFR-1) (EC 2.7.10.1) (Basic fibroblast growth factor FGFR1 BFGFR 822 receptor 1) (BFGFR) (bFGF-R-1) (Fms-like tyrosine kinase 2) (FLT-2) (N-sam) (Proto- CEK FGFBR FLG oncogene c-Fgr) (CD antigen CD331) FLT2 HBGFR P21802 FGFR2_HUMAN Fibroblast growth factor receptor 2 (FGFR-2) (EC 2.7.10.1) (K-sam) (KGFR) FGFR2 BEK KGFR 821 (Keratinocyte growth factor receptor) (CD antigen CD332) KSAM A6NKC4 FCGRC_HUMAN Putative high affinity immunoglobulin gamma Fc receptor IC (IgG Fc receptor IC) (Fc- FCGR1C IGFRC 280 gamma RIC) (FcRIC) (hFcgammaRIC) Q9H6D8 FNDC4_HUMAN Fibronectin type III domain-containing protein 4 (Fibronectin type III repeat-containing FNDC4 FRCP1 234 protein 1) UNQ6389/PRO21134 Q9P2B2 FPRP_HUMAN Prostaglandin F2 receptor negative regulator (CD9 partner 1) (CD9P-1) (Glu-Trp-Ile EWI PTGFRN CD9P1 879 motif-containing protein F) (EWI-F) (Prostaglandin F2-alpha receptor regulatory protein) EWIF FPRP (Prostaglandin F2-alpha receptor-associated protein) (CD antigen CD315) KIAA1436 Q5SZK8 FREM2_HUMAN FRAS1-related extracellular matrix protein 2 (ECM3 homolog) FREM2 3169 P22455 FGFR4_HUMAN Fibroblast growth factor receptor 4 (FGFR-4) (EC 2.7.10.1) (CD antigen CD334) FGFR4 JTK2 TKF 802 O95866 G6B_HUMAN Protein G6b G6B C6orf25 241 P49771 FLT3L_HUMAN Fms-related tyrosine kinase 3 ligand (Flt3 ligand) (Flt3L) (SL cytokine) FLT3LG 235 P59646 FXYD4_HUMAN FXYD domain-containing ion transport regulator 4 FXYD4 89 UNQ526/PRO1069 P36888 FLT3_HUMAN Receptor-type tyrosine-protein kinase FLT3 (EC 2.7.10.1) (FL cytokine receptor) (Fetal FLT3 CD135 FLK2 993 liver kinase-2) (FLK-2) (Fms-like tyrosine kinase 3) (FLT-3) (Stem cell tyrosine kinase 1) STK1 (STK-1) (CD antigen CD135) Q8NAU1 FNDC5_HUMAN Fibronectin type III domain-containing protein 5 (Fibronectin type III repeat-containing FNDC5 FRCP2 212 protein 2) [Cleaved into: Irisin] Q86XX4 FRAS1_HUMAN Extracellular matrix protein FRAS1 FRAS1 KIAA1500 4008 P09958 FURIN_HUMAN Furin (EC 3.4.21.75) (Dibasic-processing enzyme) (Paired basic amino acid residue- FURIN FUR PACE 794 cleaving enzyme) (PACE) PCSK3 Q14802 FXYD3_HUMAN FXYD domain-containing ion transport regulator 3 (Chloride conductance inducer protein FXYD3 MAT8 PLML 87 Mat-8) (Mammary tumor 8 kDa protein) (Phospholemman-like) Q9H0Q3 FXYD6_HUMAN FXYD domain-containing ion transport regulator 6 (Phosphohippolin) FXYD6 95 UNQ521/PRO1056 Q96DB9 FXYD5_HUMAN FXYD domain-containing ion transport regulator 5 (Dysadherin) FXYD5 DYSAD 178 IWU1 HSPC113 UNQ2561/PRO6241 P58550 FXYD8_HUMAN Putative FXYD domain-containing ion transport regulator 8 FXYD6P3 FXYD8 94 I3L273 GFY_HUMAN Golgi-associated olfactory signaling regulator (Protein Goofy) GFY 518 P06028 GLPB_HUMAN Glycophorin-B (PAS-3) (SS-active sialoglycoprotein) (Sialoglycoprotein delta) (CD GYPB GPB 91 antigen CD235b) P10912 GHR_HUMAN Growth hormone receptor (GH receptor) (Somatotropin receptor) [Cleaved into: Growth GHR 638 hormone-binding protein (GH-binding protein) (GHBP) (Serum-binding protein)] P15421 GLPE_HUMAN Glycophorin-E GYPE GPE 78 P13224 GP1BB_HUMAN Platelet glycoprotein Ib beta chain (GP-Ib beta) (GPIb-beta) (GPIbB) (Antigen CD42b- GP1BB 206 beta) (CD antigen CD42c) Q9NU53 GINM1_HUMAN Glycoprotein integral membrane protein 1 GINM1 C6orf72 330 UNQ710/PRO1361 P02724 GLPA_HUMAN Glycophorin-A (MN sialoglycoprotein) (PAS-2) (Sialoglycoprotein alpha) (CD antigen GYPA GPA 150 CD235a) Q3T906 GNPTA_HUMAN N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (EC 2.7.8.17) (GlcNAc- GNPTAB GNPTA 1256 1-phosphotransferase subunits alpha/beta) (Stealth protein GNPTAB) (UDP-N- KIAA1208 acetylglucosamine-1-phosphotransferase subunits alpha/beta) [Cleaved into: N- acetylglucosamine-1-phosphotransferase subunit alpha; N-acetylglucosamine-1- phosphotransferase subunit beta] Q8WWB7 GLMP_HUMAN Glycosylated lysosomal membrane protein (Lysosomal protein NCU-G1) GLMP C1orf85 406 PSEC0030 UNQ2553/PRO6182 P07359 GP1BA_HUMAN Platelet glycoprotein Ib alpha chain (GP-Ib alpha) (GPIb-alpha) (GPIbA) (Glycoprotein GP1BA 652 Ibalpha) (Antigen CD42b-alpha) (CD antigen CD42b) [Cleaved into: Glycocalicin] P40197 GPV_HUMAN Platelet glycoprotein V (GPV) (Glycoprotein 5) (CD antigen CD42d) GP5 560 Q99795 GPA33_HUMAN Cell surface A33 antigen (Glycoprotein A33) GPA33 319 P14770 GPIX_HUMAN Platelet glycoprotein IX (GP-IX) (GPIX) (Glycoprotein 9) (CD antigen CD42a) GP9 177 Q86XS8 GOLI_HUMAN E3 ubiquitin-protein ligase RNF130 (EC 6.3.2.—) (Goliath homolog) (H-Goliath) (RING RNF130 419 finger protein 130) P25092 GUC2C_HUMAN Heat-stable enterotoxin receptor (STA receptor) (hSTAR) (EC 4.6.1.2) (Guanylyl cyclase GUCY2C GUC2C 1073 C) (GC-C) (Intestinal guanylate cyclase) STAR Q14789 GOGB1_HUMAN Golgin subfamily B member 1 (372 kDa Golgi complex-associated protein) (GCP372) GOLGB1 3259 (Giantin) (Macrogolgin) Q14956 GPNMB_HUMAN Transmembrane glycoprotein NMB (Transmembrane glycoprotein HGFIN) GPNMB HGFIN 572 NMB UNQ1725/PRO9925 P51841 GUC2F_HUMAN Retinal guanylyl cyclase 2 (RETGC-2) (EC 4.6.1.2) (Guanylate cyclase 2F, retinal) GUCY2F GUC2F 1108 (Guanylate cyclase F) (GC-F) (Rod outer segment membrane guanylate cyclase 2) RETGC2 (ROS-GC2) Q92643 GPI8_HUMAN GPI-anchor transamidase (GPI transamidase) (EC 3.—.—.—) (GPI8 homolog) (hGPI8) PIGK GPI8 395 (Phosphatidylinositol-glycan biosynthesis class K protein) (PIG-K) Q02846 GUC2D_HUMAN Retinal guanylyl cyclase 1 (RETGC-1) (EC 4.6.1.2) (Guanylate cyclase 2D, retinal) (Rod GUCY2D CORD6 1103 outer segment membrane guanylate cyclase) (ROS-GC) GUC1A4 GUC2D RETGC RETGC1 Q9UBK5 HCST_HUMAN Hematopoietic cell signal transducer (DNAX-activation protein 10) (Membrane protein HCST DAP10 93 DAP10) (Transmembrane adapter protein KAP10) KAP10 PIK3AP UNQ587/PRO1157 Q14CZ8 HECAM_HUMAN Hepatocyte cell adhesion molecule (Protein hepaCAM) HEPACAM 416 A8MVW5 HECA2_HUMAN HEPACAM family member 2 (Mitotic kinetics regulator) HEPACAM2 MIKI 462 UNQ305/PRO346 Q9ULI3 HEG1_HUMAN Protein HEG homolog 1 HEG1 KIAA1237 1381 Q92896 GSLG1_HUMAN Golgi apparatus protein 1 (CFR-1) (Cysteine-rich fibroblast growth factor receptor) (E- GLG1 CFR1 ESL1 1179 selectin ligand 1) (ESL-1) (Golgi sialoglycoprotein MG-160) MG160 Q99075 HBEGF_HUMAN Proheparin-binding EGF-like growth factor [Cleaved into: Heparin-binding EGF-like HBEGF DTR DTS 208 growth factor (HB-EGF) (HBEGF) (Diphtheria toxin receptor) (DT-R)] HEGFL Q96D42 HAVR1_HUMAN Hepatitis A virus cellular receptor 1 (HAVcr-1) (Kidney injury molecule 1) (KIM-1) (T-cell HAVCR1 KIM1 359 immunoglobulin and mucin domain-containing protein 1) (TIMD-1) (T-cell immunoglobulin TIM1 TIMD1 mucin receptor 1) (TIM) (TIM-1) (T-cell membrane protein 1) Q8TDQ0 HAVR2_HUMAN Hepatitis A virus cellular receptor 2 (HAVcr-2) (T-cell immunoglobulin and mucin domain- HAVCR2 TIM3 301 containing protein 3) (TIMD-3) (T-cell immunoglobulin mucin receptor 3) (TIM-3) (T-cell TIMD3 membrane protein 3) Q30201 HFE_HUMAN Hereditary hemochromatosis protein (HLA-H) HFE HLAH 348 P30511 HLAF_HUMAN HLA class I histocompatibility antigen, alpha chain F (CDA12) (HLA F antigen) HLA-F HLA-5.4 346 (Leukocyte antigen F) (MHC class I antigen F) HLAF A8MVS5 HIDE1_HUMAN Protein HIDE1 HIDE1 C19orf38 230 P13747 HLAE_HUMAN HLA class I histocompatibility antigen, alpha chain E (MHC class I antigen E) HLA-E HLA-6.2 358 HLAE Q9BQS7 HEPH_HUMAN Hephaestin (EC 1.—.—.—) HEPH KIAA0698 1158 UNQ2562/PRO6242 Q95460 HMR1_HUMAN Major histocompatibility complex class I-related gene protein (MHC class I-related gene MR1 341 protein) (Class I histocompatibility antigen-like protein) Q6MZM0 HPHL1_HUMAN Hephaestin-like protein 1 (EC 1.—.—.—) HEPHL1 1159 Q9UM44 HHLA2_HUMAN HERV-H LTR-associating protein 2 (Human endogenous retrovirus-H long terminal HHLA2 414 repeat-associating protein 2) P17693 HLAG_HUMAN HLA class I histocompatibility antigen, alpha chain G (HLA G antigen) (MHC class I HLA-G HLA-6.0 338 antigen G) HLAG Q08334 I10R2_HUMAN Interleukin-10 receptor subunit beta (IL-10 receptor subunit beta) (IL-10R subunit beta) IL10RB CRFB4 325 (IL-10RB) (Cytokine receptor class-II member 4) (Cytokine receptor family 2 member 4) D21S58 D21S66 (CRF2-4) (Interleukin-10 receptor subunit 2) (IL-10R subunit 2) (IL-10R2) (CD antigen CDw210b) Q96F46 I17RA_HUMAN Interleukin-17 receptor A (IL-17 receptor A) (IL-17RA) (CDw217) (CD antigen CD217) IL17RA IL17R 866 Q99665 I12R2_HUMAN Interleukin-12 receptor subunit beta-2 (IL-12 receptor subunit beta-2) (IL-12R subunit IL12RB2 862 beta-2) (IL-12R-beta-2) (IL-12RB2) Q14627 I13R2_HUMAN Interleukin-13 receptor subunit alpha-2 (IL-13 receptor subunit alpha-2) (IL-13R subunit IL13RA2 IL13R 380 alpha-2) (IL-13R-alpha-2) (IL-13RA2) (Interleukin-13-binding protein) (CD antigen CD213a2) Q9NRM6 I17RB_HUMAN Interleukin-17 receptor B (IL-17 receptor B) (IL-17RB) (Cytokine receptor-like 4) (IL-17 IL17RB CRL4 502 receptor homolog 1) (IL-17RM) (IL17Rh1) (Interleukin-17B receptor) (IL-17B receptor) EVI27 IL17BR UNQ2501/PRO19612 Q8NFM7 I17RD_HUMAN Interleukin-17 receptor D (IL-17 receptor D) (IL-17RD) (IL17Rhom) (Interleukin-17 IL17RD IL17RLM 739 receptor-like protein) (Set homolog) (hSef) SEF UNQ6115/PRO20026 Q8N6P7 I22R1_HUMAN Interleukin-22 receptor subunit alpha-1 (IL-22 receptor subunit alpha-1) (IL-22R-alpha-1) IL22RA1 IL22R 574 (IL-22RA1) (Cytokine receptor class-II member 9) (Cytokine receptor family 2 member 9) (CRF2-9) (ZcytoR11) Q9UMF0 ICAM5_HUMAN Intercellular adhesion molecule 5 (ICAM-5) (Telencephalin) ICAM5 TLCN TLN 924 P42701 I12R1_HUMAN Interleukin-12 receptor subunit beta-1 (IL-12 receptor subunit beta-1) (IL-12R subunit IL12RB1 IL12R 662 beta-1) (IL-12R-beta-1) (IL-12RB1) (IL-12 receptor beta component) (CD antigen CD212) IL12RB P78552 I13R1_HUMAN Interleukin-13 receptor subunit alpha-1 (IL-13 receptor subunit alpha-1) (IL-13R subunit IL13RA1 IL13R 427 alpha-1) (IL-13R-alpha-1) (IL-13RA1) (Cancer/testis antigen 19) (CT19) (CD antigen IL13RA CD213a1) Q8NFR9 I17RE_HUMAN Interleukin-17 receptor E (IL-17 receptor E) (IL-17RE) IL17RE 667 UNQ3056/PRO9877 O95256 I18RA_HUMAN Interleukin-18 receptor accessory protein (IL-18 receptor accessory protein) (IL-18RAcP) IL18RAP IL1R7 599 (Accessory protein-like) (AcPL) (CD218 antigen-like family member B) (CDw218b) (IL-1R accessory protein-like) (IL-1RAcPL) (Interleukin-1 receptor 7) (IL-1R-7) (IL-1R7) (Interleukin-18 receptor accessory protein-like) (Interleukin-18 receptor beta) (IL-18R- beta) (IL-18Rbeta) (CD antigen CD218b) Q6UXL0 I20RB_HUMAN Interleukin-20 receptor subunit beta (IL-20 receptor subunit beta) (IL-20R-beta) (IL-20RB) IL20RB DIRS1 311 (Fibronectin type III domain containing 6) (FNDC6) (IL-20R2) UNQ557/PRO1114 P32942 ICAM3_HUMAN Intercellular adhesion molecule 3 (ICAM-3) (CDw50) (ICAM-R) (CD antigen CD50) ICAM3 547 Q13261 I15RA_HUMAN Interleukin-15 receptor subunit alpha (IL-15 receptor subunit alpha) (IL-15R-alpha) (IL- IL15RA 267 15RA) (CD antigen CD215) [Cleaved into: Soluble interleukin-15 receptor subunit alpha (sIL-15 receptor subunit alpha) (sIL-15R-alpha) (sIL-15RA)] Q9H2X8 I27L2_HUMAN Interferon alpha-inducible protein 27-like protein 2 (Interferon-stimulated gene 12b IFI27L2 FAM14A 130 protein) (ISG12(b)) (Protein TLH29) (pIFI27-like protein) TLH29 Q9Y6W8 ICOS_HUMAN Inducible T-cell costimulator (Activation-inducible lymphocyte immunomediatory ICOS AILIM 199 molecule) (CD antigen CD278) P13598 ICAM2_HUMAN Intercellular adhesion molecule 2 (ICAM-2) (CD antigen CD102) ICAM2 275 P98153 IDD_HUMAN Integral membrane protein DGCR2/IDD DGCR2 IDD 550 KIAA0163 O75054 IGSF3_HUMAN Immunoglobulin superfamily member 3 (IgSF3) (Glu-Trp-Ile EWI motif-containing protein IGSF3 EWI3 1194 3) (EWI-3) KIAA0466 P01589 IL2RA_HUMAN Interleukin-2 receptor subunit alpha (IL-2 receptor subunit alpha) (IL-2-RA) (IL-2R subunit IL2RA 272 alpha) (IL2-RA) (TAC antigen) (p55) (CD antigen CD25) P26951 IL3RA_HUMAN Interleukin-3 receptor subunit alpha (IL-3 receptor subunit alpha) (IL-3R subunit alpha) IL3RA IL3R 378 (IL-3R-alpha) (IL-3RA) (CD antigen CD123) P24394 IL4RA_HUMAN Interleukin-4 receptor subunit alpha (IL-4 receptor subunit alpha) (IL-4R subunit alpha) IL4R IL4RA 582J2.1 825 (IL-4R-alpha) (IL-4RA) (CD antigen CD124) [Cleaved into: Soluble interleukin-4 receptor subunit alpha (Soluble IL-4 receptor subunit alpha) (Soluble IL-4R-alpha) (sIL4Ralpha/prot) (IL-4-binding protein) (IL4-BP)] Q8NAC3 I17RC_HUMAN Interleukin-17 receptor C (IL-17 receptor C) (IL-17RC) (Interleukin-17 receptor homolog) IL17RC 791 (IL17Rhom) (Interleukin-17 receptor-like protein) (IL-17RL) (ZcytoR14) UNQ6118/PRO20040/ PRO38901 Q9UHF4 I20RA_HUMAN Interleukin-20 receptor subunit alpha (IL-20 receptor subunit alpha) (IL-20R-alpha) (IL- IL20RA 553 20RA) (Cytokine receptor class-II member 8) (Cytokine receptor family 2 member 8) UNQ681/PRO1315 (CRF2-8) (IL-20R1) (ZcytoR7) Q6UWB1 I27RA_HUMAN Interleukin-27 receptor subunit alpha (IL-27 receptor subunit alpha) (IL-27R subunit IL27RA CRL1 636 alpha) (IL-27R-alpha) (IL-27RA) (Cytokine receptor WSX-1) (Cytokine receptor-like 1) TCCR WSX1 (Type I T-cell cytokine receptor) (TCCR) (ZcytoR1) UNQ296/PRO336 Q9H665 IGFR1_HUMAN IGF-like family receptor 1 (Transmembrane protein 149) (U2 small nuclear RNA auxiliary IGFLR1 TMEM149 355 factor 1-like 4) U2AF1L4 P01880 IGHD_HUMAN Ig delta chain C region IGHD 384 Q5DX21 IGS11_HUMAN Immunoglobulin superfamily member 11 (IgSF11) (Brain and testis-specific IGSF11 BTIGSF 431 immunoglobulin superfamily protein) (Bt-IGSF) (V-set and immunoglobulin domain- CXADRL1 VSIG3 containing protein 3) Q93033 IGSF2_HUMAN Immunoglobulin superfamily member 2 (IgSF2) (Cell surface glycoprotein V7) (Glu-Trp-Ile CD101 EWI101 1021 EWI motif-containing protein 101) (EWI-101) (CD antigen CD101) IGSF2 V7 Q9HBE5 IL21R_HUMAN Interleukin-21 receptor (IL-21 receptor) (IL-21R) (Novel interleukin receptor) (CD antigen IL21R NILR 538 CD360) UNQ3121/PRO10273 Q71H61 ILDR2_HUMAN Immunoglobulin-like domain-containing receptor 2 ILDR2 C1orf32 639 O75144 ICOSL_HUMAN ICOS ligand (B7 homolog 2) (B7-H2) (B7-like protein GI50) (B7-related protein 1) (B7RP- ICOSLG B7H2 302 1) (CD antigen CD275) B7RP1 ICOSL KIAA0653 Q8TDY8 IGDC4_HUMAN Immunoglobulin superfamily DCC subclass member 4 (Neighbor of punc e11) (Protein IGDCC4 DDM36 1250 DDM36) (hDDM36) KIAA1628 NOPE P01871 IGHM_HUMAN Ig mu chain C region IGHM 452 O95976 IGSF6_HUMAN Immunoglobulin superfamily member 6 (IgSF6) (Protein DORA) IGSF6 DORA 241 Q9NPH3 IL1AP_HUMAN Interleukin-1 receptor accessory protein (IL-1 receptor accessory protein) (IL-1RAcP) IL1RAP C3orf13 570 (Interleukin-1 receptor 3) (IL-1R-3) (IL-1R3) IL1R3 P31785 IL2RG_HUMAN Cytokine receptor common subunit gamma (Interleukin-2 receptor subunit gamma) (IL-2 IL2RG 369 receptor subunit gamma) (IL-2R subunit gamma) (IL-2RG) (gammaC) (p64) (CD antigen CD132) P32927 IL3RB_HUMAN Cytokine receptor common subunit beta (CDw131) (GM-CSF/IL-3/IL-5 receptor common CSF2RB IL3RB 897 beta subunit) (CD antigen CD131) IL5RB Q01113 IL9R_HUMAN Interleukin-9 receptor (IL-9 receptor) (IL-9R) (CD antigen CD129) IL9R 521 Q9HB29 ILRL2_HUMAN Interleukin-1 receptor-like 2 (IL-36 receptor) (IL-36R) (Interleukin-1 receptor-related IL1RL2 IL1RRP2 575 protein 2) (IL-1Rrp2) (IL1R-rp2) P15260 INGR1_HUMAN Interferon gamma receptor 1 (IFN-gamma receptor 1) (IFN-gamma-R1) (CDw119) (CD IFNGR1 489 antigen CD119) Q13651 I10R1_HUMAN Interleukin-10 receptor subunit alpha (IL-10 receptor subunit alpha) (IL-10R subunit IL10RA IL10R 578 alpha) (IL-10RA) (CDw210a) (Interleukin-10 receptor subunit 1) (IL-10R subunit 1) (IL- 10R1) (CD antigen CD210) Q14626 I11RA_HUMAN Interleukin-11 receptor subunit alpha (IL-11 receptor subunit alpha) (IL-11R subunit IL11RA 422 alpha) (IL-11R-alpha) (IL-11RA) P05362 ICAM1_HUMAN Intercellular adhesion molecule 1 (ICAM-1) (Major group rhinovirus receptor) (CD antigen ICAM1 532 CD54) Q14773 ICAM4_HUMAN Intercellular adhesion molecule 4 (ICAM-4) (Landsteiner-Wiener blood group ICAM4 LW 271 glycoprotein) (LW blood group protein) (CD antigen CD242) Q9NSI5 IGSF5_HUMAN Immunoglobulin superfamily member 5 (IgSF5) (Junctional adhesion molecule 4) (JAM-4) IGSF5 JAM4 407 P14778 IL1R1_HUMAN Interleukin-1 receptor type 1 (IL-1R-1) (IL-1RT-1) (IL-1RT1) (CD121 antigen-like family IL1R1 IL1R IL1RA 569 member A) (Interleukin-1 receptor alpha) (IL-1R-alpha) (Interleukin-1 receptor type I) IL1RT1 (p80) (CD antigen CD121a) [Cleaved into: Interleukin-1 receptor type 1, membrane form (mIL-1R1) (mIL-1RI); Interleukin-1 receptor type 1, soluble form (sIL-1R1) (sIL-1RI)] Q8NI17 IL31R_HUMAN Interleukin-31 receptor subunit alpha (IL-31 receptor subunit alpha) (IL-31R subunit IL31RA CRL3 GPL 732 alpha) (IL-31R-alpha) (IL-31RA) (Cytokine receptor-like 3) (GLM-R) (hGLM-R) (Gp130- UNQ6368/PRO21073/ like monocyte receptor) (Gp130-like receptor) (ZcytoR17) PRO21384 Q01344 IL5RA_HUMAN Interleukin-5 receptor subunit alpha (IL-5 receptor subunit alpha) (IL-5R subunit alpha) IL5RA IL5R 420 (IL-5R-alpha) (IL-5RA) (CDw125) (CD antigen CD125) P16871 IL7RA_HUMAN Interleukin-7 receptor subunit alpha (IL-7 receptor subunit alpha) (IL-7R subunit alpha) IL7R 459 (IL-7R-alpha) (IL-7RA) (CDw127) (CD antigen CD127) P08887 IL6RA_HUMAN Interleukin-6 receptor subunit alpha (IL-6 receptor subunit alpha) (IL-6R subunit alpha) IL6R 468 (IL-6R-alpha) (IL-6RA) (IL-6R 1) (Membrane glycoprotein 80) (gp80) (CD antigen CD126) Q01638 ILRL1_HUMAN Interleukin-1 receptor-like 1 (Protein ST2) IL1RL1 DER4 ST2 556 T1 P06213 INSR_HUMAN Insulin receptor (IR) (EC 2.7.10.1) (CD antigen CD220) [Cleaved into: Insulin receptor INSR 1382 subunit alpha; Insulin receptor subunit beta] P08069 IGF1R_HUMAN Insulin-like growth factor 1 receptor (EC 2.7.10.1) (Insulin-like growth factor I receptor) IGF1R 1367 (IGF-I receptor) (CD antigen CD221) [Cleaved into: Insulin-like growth factor 1 receptor alpha chain; Insulin-like growth factor 1 receptor beta chain] P14784 IL2RB_HUMAN Interleukin-2 receptor subunit beta (IL-2 receptor subunit beta) (IL-2R subunit beta) (IL- IL2RB 551 2RB) (High affinity IL-2 receptor subunit beta) (p70-75) (p75) (CD antigen CD122) Q86SU0 ILDR1_HUMAN Immunoglobulin-like domain-containing receptor 1 ILDR1 546 P14616 INSRR_HUMAN Insulin receptor-related protein (IRR) (EC 2.7.10.1) (IR-related receptor) [Cleaved into: INSRR IRR 1297 Insulin receptor-related protein alpha chain; Insulin receptor-related protein beta chain] Q13478 IL18R_HUMAN Interleukin-18 receptor 1 (IL-18R-1) (IL-18R1) (CD218 antigen-like family member A) IL18R1 IL1RRP 541 (CDw218a) (IL1 receptor-related protein) (IL-1Rrp) (IL1R-rp) (CD antigen CD218a) Q5VWK5 IL23R_HUMAN Interleukin-23 receptor (IL-23 receptor) (IL-23R) IL23R 629 Q9BZV3 IMPG2_HUMAN Interphotoreceptor matrix proteoglycan 2 (Interphotoreceptor matrix proteoglycan of 200 IMPG2 IPM200 1241 kDa) (IPM 200) (Sialoprotein associated with cones and rods proteoglycan) (Spacrcan) Q8IU57 INLR1_HUMAN Interferon lambda receptor 1 (IFN-lambda receptor 1) (IFN-lambda-R1) (Cytokine IFNLR1 IL28RA 520 receptor class-11 member 12) (Cytokine receptor family 2 member 12) (CRF2-12) LICR2 (Interleukin-28 receptor subunit alpha) (IL-28 receptor subunit alpha) (IL-28R-alpha) (IL- 28RA) (Likely interleukin or cytokine receptor 2) (LICR2) Q6GPH6 IPIL1_HUMAN Inositol 1,4,5-trisphosphate receptor-interacting protein-like 1 ITPRIPL1 555 KIAA1754L Q9NP60 IRPL2_HUMAN X-linked interleukin-1 receptor accessory protein-like 2 (IL-1 receptor accessory protein- IL1RAPL2 IL1R9 686 like 2) (IL-1-RAPL-2) (IL-1RAPL-2) (IL1RAPL-2) (IL1RAPL-2-related protein) (Interleukin- 1 receptor 9) (IL-1R-9) (IL-1R9) (Three immunoglobulin domain-containing IL-1 receptor- related 1) (TIGIRR-1) Q8IVU1 IGDC3_HUMAN Immunoglobulin superfamily DCC subclass member 3 (Putative neuronal cell adhesion IGDCC3 PUNC 814 molecule) P17181 INAR1_HUMAN Interferon alpha/beta receptor 1 (IFN-R-1) (IFN-alpha/beta receptor 1) (Cytokine receptor IFNAR1 IFNAR 557 class-II member 1) (Cytokine receptor family 2 member 1) (CRF2-1) (Type I interferon receptor 1) Q13683 ITA7_HUMAN Integrin alpha-7 [Cleaved into: Integrin alpha-7 heavy chain; Integrin alpha-7 light chain; ITGA7 1181 Integrin alpha-7 70 kDa form] UNQ406/PRO768 P53708 ITA8_HUMAN Integrin alpha-8 [Cleaved into: Integrin alpha-8 heavy chain; Integrin alpha-8 light chain] ITGA8 1063 Q13349 ITAD_HUMAN Integrin alpha-D (ADB2) (CD11 antigen-like family member D) (Leukointegrin alpha D) ITGAD 1161 (CD antigen CD11d) P06756 ITAV_HUMAN Integrin alpha-V (Vitronectin receptor subunit alpha) (CD antigen CD51) [Cleaved into: ITGAV MSK8 VNRA 1048 Integrin alpha-V heavy chain; Integrin alpha-V light chain] Q6UXV1 IZUM2_HUMAN Izumo sperm-egg fusion protein 2 IZUMO2 C19orf41 221 SCRL UNQ6978/PRO21961 P27930 IL1R2_HUMAN Interleukin-1 receptor type 2 (IL-1R-2) (IL-1RT-2) (IL-1RT2) (CD121 antigen-like family IL1R2 IL1RB 398 member B) (CDw121b) (IL-1 type II receptor) (Interleukin-1 receptor beta) (IL-1R-beta) (Interleukin-1 receptor type II) (CD antigen CD121b) [Cleaved into: Interleukin-1 receptor type 2, membrane form (mIL-1R2) (mIL-1RII); Interleukin-1 receptor type 2, soluble form (sIL-1R2) (sIL-1RII)] P40189 IL6RB_HUMAN Interleukin-6 receptor subunit beta (IL-6 receptor subunit beta) (IL-6R subunit beta) (IL- IL6ST 918 6R-beta) (IL-6RB) (CDw130) (Interleukin-6 signal transducer) (Membrane glycoprotein 130) (gp130) (Oncostatin-M receptor subunit alpha) (CD antigen CD130) P17301 ITA2_HUMAN Integrin alpha-2 (CD49 antigen-like family member B) (Collagen receptor) (Platelet ITGA2 CD49B 1181 membrane glycoprotein Ia) (GPIa) (VLA-2 subunit alpha) (CD antigen CD49b) P26006 ITA3_HUMAN Integrin alpha-3 (CD49 antigen-like family member C) (FRP-2) (Galactoprotein B3) ITGA3 MSK18 1051 (GAPB3) (VLA-3 subunit alpha) (CD antigen CD49c) [Cleaved into: Integrin alpha-3 heavy chain; Integrin alpha-3 light chain] P11215 ITAM_HUMAN Integrin alpha-M (CD11 antigen-like family member B) (CR-3 alpha chain) (Cell surface ITGAM CD11B 1152 glycoprotein MAC-1 subunit alpha) (Leukocyte adhesion receptor M01) (Neutrophil CR3A adherence receptor) (CD antigen CD11b) P16144 ITB4_HUMAN Integrin beta-4 (GP150) (CD antigen CD104) ITGB4 1822 O75578 ITA10_HUMAN Integrin alpha-10 ITGA10 1167 UNQ468/PRO827 P56199 ITA1_HUMAN Integrin alpha-1 (CD49 antigen-like family member A) (Laminin and collagen receptor) ITGA1 1179 (VLA-1) (CD antigen CD49a) P08514 ITA2B_HUMAN Integrin alpha-IIb (GPalpha IIb) (GPIIb) (Platelet membrane glycoprotein IIb) (CD antigen ITGA2B GP2B 1039 CD41) [Cleaved into: Integrin alpha-IIb heavy chain; Integrin alpha-IIb light chain, form 1; ITGAB Integrin alpha-IIb light chain, form 2] P08648 ITA5_HUMAN Integrin alpha-5 (CD49 antigen-like family member E) (Fibronectin receptor subunit alpha) ITGA5 FNRA 1049 (Integrin alpha-F) (VLA-5) (CD antigen CD49e) [Cleaved into: Integrin alpha-5 heavy chain; Integrin alpha-5 light chain] P38570 ITAE_HUMAN Integrin alpha-E (HML-1 antigen) (Integrin alpha-IEL) (Mucosal lymphocyte 1 antigen) ITGAE 1179 (CD antigen CD103) [Cleaved into: Integrin alpha-E light chain: Integrin alpha-E heavy chain] P20702 ITAX_HUMAN Integrin alpha-X (CD11 antigen-like family member C) (Leu M5) (Leukocyte adhesion ITGAX CD11C 1163 glycoprotein p150, 95 alpha chain) (Leukocyte adhesion receptor p150, 95) (CD antigen CD11c) P05106 ITB3_HUMAN Integrin beta-3 (Platelet membrane glycoprotein IIIa) (GPIIIa) (CD antigen CD61) ITGB3 GP3A 788 Q5VZ72 IZUM3_HUMAN Izumo sperm-egg fusion protein 3 IZUMO3 C9orf134 239 P78504 JAG1_HUMAN Protein jagged-1 (Jagged1) (hJ1) (CD antigen CD339) JAG1 JAGL1 1218 A8MWY0 K132L_HUMAN UPF0577 protein KIAA1324-like (Estrogen-induced gene 121-like protein) (hEIG121L) KIAA1324L 1029 EIG121L P48551 INAR2_HUMAN Interferon alpha/beta receptor 2 (IFN-R-2) (IFN-alpha binding protein) (IFN-alpha/beta IFNAR2 IFNABR 515 receptor 2) (Interferon alpha binding protein) (Type I interferon receptor 2) IFNARB P38484 INGR2_HUMAN Interferon gamma receptor 2 (IFN-gamma receptor 2) (IFN-gamma-R2) (Interferon IFNGR2 IFNGT1 337 gamma receptor accessory factor 1) (AF-1) (Interferon gamma transducer 1) Q3MIP1 IPIL2_HUMAN Inositol 1,4,5-trisphosphate receptor-interacting protein-like 2 ITPRIPL2 535 Q6UXG2 K1324_HUMAN UPF0577 protein KIAA1324 (Estrogen-induced gene 121 protein) KIAA1324 EIG121 1013 UNQ2426/PRO4985 Q3SXP7 K1644_HUMAN Uncharacterized protein KIAA1644 KIAA1644 199 Q9NZN1 IRPL1_HUMAN Interleukin-1 receptor accessory protein-like 1 (IL-1-RAPL-1) (IL-1RAPL-1) (IL1RAPL-1) IL1RAPL1 OPHN4 696 (Oligophrenin-4) (Three immunoglobulin domain-containing IL-1 receptor-related 2) (TIGIRR-2) (X-linked interleukin-1 receptor accessory protein-like 1) Q9UKX5 ITA11_HUMAN Integrin alpha-11 ITGA11 MSTP018 1188 P05556 ITB1_HUMAN Integrin beta-1 (Fibronectin receptor subunit beta) (Glycoprotein IIa) (GPIIA) (VLA-4 ITGB1 FNRB MDF2 798 subunit beta) (CD antigen CD29) MSK12 P05107 ITB2_HUMAN Integrin beta-2 (Cell surface adhesion glycoproteins LFA-1/CR3/p150, 95 subunit beta) ITGB2 CD18 MFI7 769 (Complement receptor C3 subunit beta) (CD antigen CD18) P18564 ITB6_HUMAN Integrin beta-6 ITGB6 788 P26010 ITB7_HUMAN Integrin beta-7 (Gut homing receptor beta subunit) ITGB7 798 P26012 ITB8_HUMAN Integrin beta-8 ITGB8 769 Q9Y624 JAM1_HUMAN Junctional adhesion molecule A (JAM-A) (Junctional adhesion molecule 1) (JAM-1) F11R JAM1 JCAM 299 (Platelet F11 receptor) (Platelet adhesion molecule 1) (PAM-1) (CD antigen CD321) UNQ264/PRO301 Q9BX67 JAM3_HUMAN Junctional adhesion molecule C (JAM-C) (JAM-2) (Junctional adhesion molecule 3) JAM3 310 (JAM-3) UNQ859/PRO1868 Q8IYV9 IZUM1_HUMAN Izumo sperm-egg fusion protein 1 (Oocyte binding/fusion factor) (OBF) (Sperm-specific IZUMO1 350 protein izumo) Q9UJ90 KCNE5_HUMAN Potassium voltage-gated channel subfamily E regulatory beta subunit 5 (AMME KCNE5 AMMECR2 142 syndrome candidate gene 2 protein) (Potassium channel subunit beta MiRP4) (Potassium KCNE1L voltage-gated channel subfamily E member 1-like protein) P13612 ITA4_HUMAN Integrin alpha-4 (CD49 antigen-like family member D) (Integrin alpha-IV) (VLA-4 subunit ITGA4 CD49D 1032 alpha) (CD antigen CD49d) P23229 ITA6_HUMAN Integrin alpha-6 (CD49 antigen-like family member F) (VLA-6) (CD antigen CD49f) ITGA6 1130 [Cleaved into: Integrin alpha-6 heavy chain; Integrin alpha-6 light chain; Processed integrin alpha-6 (Alpha6p)] Q13797 ITA9_HUMAN Integrin alpha-9 (Integrin alpha-RLC) ITGA9 1035 P20701 ITAL_HUMAN Integrin alpha-L (CD11 antigen-like family member A) (Leukocyte adhesion glycoprotein ITGAL CD11A 1170 LFA-1 alpha chain) (LFA-1A) (Leukocyte function-associated molecule 1 alpha chain) (CD antigen CD11a) P18084 ITB5_HUMAN Integrin beta-5 ITGB5 799 Q9Y219 JAG2_HUMAN Protein jagged-2 (Jagged2) (hJ2) JAG2 1238 Q5VV43 K0319_HUMAN Dyslexia-associated protein KIAA0319 KIAA0319 1072 Q8IYS2 K2013_HUMAN Uncharacterized protein KIAA2013 KIAA2013 634 P57087 JAM2_HUMAN Junctional adhesion molecule B (JAM-B) (Junctional adhesion molecule 2) (JAM-2) JAM2 C21orf43 298 (Vascular endothelial junction-associated molecule) (VE-JAM) (CD antigen CD322) VEJAM UNQ219/PRO245 Q86YT9 JAML_HUMAN Junctional adhesion molecule-like (Adhesion molecule interacting with CXADR antigen 1) JAML AMICA1 394 (Dendritic cell-specific protein CREA7-1) UNQ722/PRO1387 A0A087 KCE1B_HUMAN Potassium voltage-gated channel subfamily E member 1B KCNE1B 132 WTH5 Q8NC54 KCT2_HUMAN Keratinocyte-associated transmembrane protein 2 KCT2 C5orf15 265 HTGN29 Q6UWL6 KIRR2_HUMAN Kin of IRRE-like protein 2 (Kin of irregular chiasm-like protein 2) (Nephrin-like protein 3) KIRREL2 NEPH3 708 UNQ5827/PRO19646 O76095 JTB_HUMAN Protein JTB (Jumping translocation breakpoint protein) (Prostate androgen-regulated JTB HSPC222 146 protein) (PAR protein) Q9Y6J6 KCNE2_HUMAN Potassium voltage-gated channel subfamily E member 2 (MinK-related peptide 1) KCNE2 123 (Minimum potassium ion channel-related peptide 1) (Potassium channel subunit beta MiRP1) Q9Y6H6 KCNE3_HUMAN Potassium voltage-gated channel subfamily E member 3 (MinK-related peptide 2) KCNE3 103 (Minimum potassium ion channel-related peptide 2) (Potassium channel subunit beta MiRP2) Q8NHK3 KI2LB_HUMAN Killer cell immunoglobulin-like receptor 2DL5B (CD158 antigen-like family member F2) KIR2DL5B CD158F 375 (Killer cell immunoglobulin-like receptor 2DLX) (CD antigen CD158f2) CD158F2 KIR2DL5 KIR2DLX Q14952 KI2S3_HUMAN Killer cell immunoglobulin-like receptor 2DS3 (MHC class I NK cell receptor) (Natural KIR2DS3 NKAT7 304 killer-associated transcript 7) (NKAT-7) Q14943 KI3S1_HUMAN Killer cell immunoglobulin-like receptor 3DS1 (MHC class I NK cell receptor) (Natural KIR3DS1 NKAT10 387 killer-associated transcript 10) (NKAT-10) Q9NRX6 KISHB_HUMAN Protein kish-B (Transmembrane protein 167B) TMEM167B 74 C1orf119 AD-020 P15382 KCNE1_HUMAN Potassium voltage-gated channel subfamily E member 1 (Delayed rectifier potassium KCNE1 129 channel subunit IsK) (IKs producing slow voltage-gated potassium channel subunit beta Mink) (Minimal potassium channel) P43626 KI2L1_HUMAN Killer cell immunoglobulin-like receptor 2DL1 (CD158 antigen-like family member A) KIR2DL1 CD158A 348 (MHC class I NK cell receptor) (Natural killer-associated transcript 1) (NKAT-1) (p58 NKAT1 natural killer cell receptor clones CL-42/47.11) (p58 NK receptor CL-42/47.11) (p58.1 MHC class-I-specific NK receptor) (CD antigen CD158a) Q99706 KI2L4_HUMAN Killer cell immunoglobulin-like receptor 2DL4 (CD158 antigen-like family member D) KIR2DL4 CD158D 377 (G9P) (Killer cell inhibitory receptor 103AS) (KIR-103AS) (MHC class I NK cell receptor KIR103AS KIR103AS) (CD antigen CD158d) P43632 KI2S4_HUMAN Killer cell immunoglobulin-like receptor 2DS4 (CD158 antigen-like family member I) (MHC KIR2DS4 CD158I 304 class I NK cell receptor) (Natural killer-associated transcript 8) (NKAT-8) (P58 natural KKA3 NKAT8 killer cell receptor clones CL-39/CL-17) (p58 NK receptor CL-39/CL-17) (CD antigen CD158i) Q8IZU9 KIRR3_HUMAN Kin of IRRE-like protein 3 (Kin of irregular chiasm-like protein 3) (Nephrin-like protein 2) KIRREL3 KIAA1867 778 [Cleaved into: Processed kin of IRRE-like protein 3] NEPH2 UNQ5923/PRO4502/ PRO19814 P32004 L1CAM_HUMAN Neural cell adhesion molecule L1 (N-CAM-L1) (NCAM-L1) (CD antigen CD171) L1CAM CAML1 1257 MIC5 Q6GTX8 LAIR1_HUMAN Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) (hLAIR1) (CD antigen LAIR1 CD305 287 CD305) P43628 KI2L3_HUMAN Killer cell immunoglobulin-like receptor 2DL3 (CD158 antigen-like family member B2) KIR2DL3 CD158B2 341 (KIR-023GB) (Killer inhibitory receptor cl 2-3) (MHC class I NK cell receptor) (NKAT2a) KIRCL23 NKAT2 (NKAT2b) (Natural killer-associated transcript 2) (NKAT-2) (p58 natural killer cell receptor clone CL-6) (p58 NK receptor CL-6) (p58.2 MHC class-I-specific NK receptor) (CD antigen CD158b2) Q14954 KI2S1_HUMAN Killer cell immunoglobulin-like receptor 2DS1 (CD158 antigen-like family member H) KIR2DS1 CD158H 304 (MHC class I NK cell receptor Eb6 Actl) (CD antigen CD158h) Q14953 KI2S5_HUMAN Killer cell immunoglobulin-like receptor 2DS5 (CD158 antigen-like family member G) KIR2DS5 CD158G 304 (MHC class I NK cell receptor) (Natural killer-associated transcript 9) (NKAT-9) (CD NKAT9 antigen CD158g) P43629 KI3L1_HUMAN Killer cell immunoglobulin-like receptor 3DL1 (CD158 antigen-like family member E) KIR3DL1 CD158E 444 (HLA-BW4-specific inhibitory NK cell receptor) (MHC class I NK cell receptor) (Natural NKAT3 NKB1 killer-associated transcript 3) (NKAT-3) (p70 natural killer cell receptor clones CL-2/CL- 11) (p70 NK receptor CL-2/CL-11) (CD antigen CD158e) Q8N743 KI3L3_HUMAN Killer cell immunoglobulin-like receptor 3DL3 (CD158 antigen-like family member Z) KIR3DL3 CD158Z 410 (Killer cell inhibitory receptor 1) (CD antigen CD158z) KIR3DL7 KIRC1 Q96J84 KIRR1_HUMAN Kin of IRRE-like protein 1 (Kin of irregular chiasm-like protein 1) (Nephrin-like protein 1) KIRREL KIRREL1 757 NEPH1 P10721 KIT_HUMAN Mast/stem cell growth factor receptor Kit (SCFR) (EC 2.7.10.1) (Piebald trait protein) KIT SCFR 976 (PBT) (Proto-oncogene c-Kit) (Tyrosine-protein kinase Kit) (p145 c-kit) (v-kit Hardy- Zuckerman 4 feline sarcoma viral oncogene homolog) (CD antigen CD117) Q86UK5 LBN_HUMAN Limbin (Ellis-van Creveld syndrome protein 2) (EVC2) EVC2 LBN 1308 P43627 KI2L2_HUMAN Killer cell immunoglobulin-like receptor 2DL2 (CD158 antigen-like family member B1) KIR2DL2 CD158B1 348 (MHC class I NK cell receptor) (Natural killer-associated transcript 6) (NKAT-6) (p58 NKAT6 natural killer cell receptor clone CL-43) (p58 NK receptor CL-43) (CD antigen CD158b1) Q8N109 KI2LA_HUMAN Killer cell immunoglobulin-like receptor 2DL5A (CD antigen CD158f1) KIR2DL5A CD158F 375 CD158F1 KIR2DL5 P43631 KI2S2_HUMAN Killer cell immunoglobulin-like receptor 2DS2 (CD158 antigen-like family member J) KIR2DS2 CD158J 304 (MHC class I NK cell receptor) (NK receptor 183 Actl) (Natural killer-associated transcript NKAT5 5) (NKAT-5) (p58 natural killer cell receptor clone CL-49) (p58 NK receptor CL-49) (CD antigen CD158j) P43630 KI3L2_HUMAN Killer cell immunoglobulin-like receptor 3DL2 (CD158 antigen-like family member K) KIR3DL2 CD158K 455 (MHC class I NK cell receptor) (Natural killer-associated transcript 4) (NKAT-4) (p70 NKAT4 natural killer cell receptor clone CL-5) (p70 NK receptor CL-5) (CD antigen CD158k) Q8TBQ9 KISHA_HUMAN Protein kish-A (Transmembrane protein 167) (Transmembrane protein 167A) TMEM167A 72 TMEM167 Q96MU8 KREM1_HUMAN Kremen protein 1 (Dickkopf receptor) (Kringle domain-containing transmembrane protein KREMEN1 473 1) (Kringle-containing protein marking the eye and the nose) KREMEN KRM1 P11279 LAMP1_HUMAN Lysosome-associated membrane glycoprotein 1 (LAMP-1) (Lysosome-associated LAMP1 417 membrane protein 1) (CD107 antigen-like family member A) (CD antigen CD107a) P13473 LAMP2_HUMAN Lysosome-associated membrane glycoprotein 2 (LAMP-2) (Lysosome-associated LAMP2 410 membrane protein 2) (CD107 antigen-like family member B) (CD antigen CD107b) P01130 LDLR_HUMAN Low-density lipoprotein receptor (LDL receptor) LDLR 860 Q9UEF7 KLOT_HUMAN Klotho (EC 3.2.1.31) [Cleaved into: Klotho peptide] KL 1012 A6NM11 L37A2_HUMAN Leucine-rich repeat-containing protein 37A2 LRRC37A2 1700 Q9UJQ1 LAMP5_HUMAN Lysosome-associated membrane glycoprotein 5 (Brain and dendritic cell-associated LAMP5 C20orf103 280 LAMP) (Brain-associated LAMP-like protein) (BAD-LAMP) (Lysosome-associated membrane protein 5) (LAMP-5) P19256 LFA3_HUMAN Lymphocyte function-associated antigen 3 (Ag3) (Surface glycoprotein LFA-3) (CD CD58 LFA3 250 antigen CD58) Q8NCW0 KREM2_HUMAN Kremen protein 2 (Dickkopf receptor 2) (Kringle domain-containing transmembrane KREMEN2 KRM2 462 protein 2) (Kringle-containing protein marking the eye and the nose) A6NMS7 L37A1_HUMAN Leucine-rich repeat-containing protein 37A LRRC37A 1700 LRRC37A1 O60309 L37A3_HUMAN Leucine-rich repeat-containing protein 37A3 LRRC37A3 1634 KIAA0563 P18627 LAG3_HUMAN Lymphocyte activation gene 3 protein (LAG-3) (Protein FDC) (CD antigen CD223) LAG3 FDC 525 Q6UX15 LAYN_HUMAN Layilin LAYN 382 UNQ208/PRO234 P48357 LEPR_HUMAN Leptin receptor (LEP-R) (HuB219) (OB receptor) (OB-R) (CD antigen CD295) LEPR DB OBR 1165 Q8N149 LIRA2_HUMAN Leukocyte immunoglobulin-like receptor subfamily A member 2 (CD85 antigen-like family LILRA2 ILT1 LIR7 483 member H) (Immunoglobulin-like transcript 1) (ILT-1) (Leukocyte immunoglobulin-like receptor 7) (LIR-7) (CD antigen CD85h) A6NI73 LIRA5_HUMAN Leukocyte immunoglobulin-like receptor subfamily A member 5 (CD85 antigen-like family LILRA5 ILT11 299 member F) (Immunoglobulin-like transcript 11) (ILT-11) (Leukocyte immunoglobulin-like LILRB7 LIR9 receptor 9) (LIR-9) (CD antigen CD85f) Q8N423 LIRB2_HUMAN Leukocyte immunoglobulin-like receptor subfamily B member 2 (LIR-2) (Leukocyte LILRB2 ILT4 LIR2 598 immunoglobulin-like receptor 2) (CD85 antigen-like family member D) (Immunoglobulin- MIR10 like transcript 4) (ILT-4) (Monocyte/macrophage immunoglobulin-like receptor 10) (MIR- 10) (CD antigen CD85d) P42702 LIFR_HUMAN Leukemia inhibitory factor receptor (LIF receptor) (LIF-R) (CD antigen CD118) LIFR 1097 Q6UY18 LIGO4_HUMAN Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting LINGO4 LRRN6D 593 protein 4 (Leucine-rich repeat neuronal protein 6D) UNQ9248/PRO34002 Q6PI73 LIRA6_HUMAN Leukocyte immunoglobulin-like receptor subfamily A member 6 (Immunoglobulin-like LILRA6 ILT8 481 transcript 8) (ILT-8) (Leukocyte Ig-like receptor) O75022 LIRB3_HUMAN Leukocyte immunoglobulin-like receptor subfamily B member 3 (LIR-3) (Leukocyte LILRB3 ILT5 LIR3 631 immunoglobulin-like receptor 3) (CD85 antigen-like family member A) (Immunoglobulin- like transcript 5) (ILT-5) (Monocyte inhibitory receptor HL9) (CD antigen CD85a) P49257 LMAN1_HUMAN Protein ERGIC-53 (ER-Golgi intermediate compartment 53 kDa protein) (Gp58) LMAN1 ERGIC53 510 (Intracellular mannose-specific lectin MR60) (Lectin mannose-binding 1) F5F8D Q9UQV4 LAMP3_HUMAN Lysosome-associated membrane glycoprotein 3 (LAMP-3) (Lysosomal-associated LAMP3 DCLAMP 416 membrane protein 3) (DC-lysosome-associated membrane glycoprotein) (DC LAMP) TSC403 (Protein TSC403) (CD antigen CD208) Q7L985 LIGO2_HUMAN Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting LINGO2 LERN3 606 protein 2 (Leucine-rich repeat neuronal protein 3) (Leucine-rich repeat neuronal protein LRRN6C 6C) UNQ9234/PRO31993 Q9H0V9 LMA2L_HUMAN VIP36-like protein (Lectin mannose-binding 2-like) (LMAN2-like protein) LMAN2L VIPL 348 PSEC0028 UNQ368/PRO704 P09848 LPH_HUMAN Lactase-phlorizin hydrolase (Lactase-glycosylceramidase) [Includes: Lactase (EC LCT LPH 1927 3.2.1.108); Phlorizin hydrolase (EC 3.2.1.62)] Q96FE5 LIGO1_HUMAN Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting LINGO1 LERN1 620 protein 1 (Leucine-rich repeat and immunoglobulin domain-containing protein 1) (Leucine- LRRN6A rich repeat neuronal protein 1) (Leucine-rich repeat neuronal protein 6A) UNQ201/PRO227 Q12907 LMAN2_HUMAN Vesicular integral-membrane protein VIP36 (Glycoprotein GP36b) (Lectin mannose- LMAN2 C5orf8 356 binding 2) (Vesicular integral-membrane protein 36) (VIP36) Q9H756 LRC19_HUMAN Leucine-rich repeat-containing protein 19 LRRC19 370 Q5VT99 LRC38_HUMAN Leucine-rich repeat-containing protein 38 (BK channel auxiliary gamma subunit LRRC38) LRRC38 294 A6NDA9 LRIT2_HUMAN Leucine-rich repeat, immunoglobulin-like domain and transmembrane domain-containing LRIT2 LRRC22 550 protein 2 (Leucine-rich repeat-containing protein 22) P16150 LEUK_HUMAN Leukosialin (Galactoglycoprotein) (GALGP) (Leukocyte sialoglycoprotein) (Sialophorin) SPN CD43 400 (CD antigen CD43) P0C6S8 LIGO3_HUMAN Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting LINGO3 LERN2 592 protein 3 (Leucine-rich repeat neuronal protein 2) (Leucine-rich repeat neuronal protein LRRN6B 6B) O75023 LIRB5_HUMAN Leukocyte immunoglobulin-like receptor subfamily B member 5 (CD85 antigen-like family LILRB5 LIR8 590 member C) (Leukocyte immunoglobulin-like receptor 8) (LIR-8) (CD antigen CD85c) Q9HAT1 LMA1L_HUMAN Protein ERGIC-53-like (ERGIC53-like protein) (Lectin mannose-binding 1-like) (LMAN1- LMAN1L ERGL 526 like protein) UNQ2784/PRO7174 O75197 LRP5_HUMAN Low-density lipoprotein receptor-related protein 5 (LRP-5) LRP5 LR3 LRP7 1615 O75581 LRP6_HUMAN Low-density lipoprotein receptor-related protein 6 (LRP-6) LRP6 1613 Q9H3W5 LRRN3_HUMAN Leucine-rich repeat neuronal protein 3 (Neuronal leucine-rich repeat protein 3) (NLRR-3) LRRN3 Nbla10363 708 UNQ194/PRO220 P59901 LIRA4_HUMAN Leukocyte immunoglobulin-like receptor subfamily A member 4 (CD85 antigen-like family LILRA4 ILT7 499 member G) (Immunoglobulin-like transcript 7) (ILT-7) (CD antigen CD85g) Q8NHL6 LIRB1_HUMAN Leukocyte immunoglobulin-like receptor subfamily B member 1 (LIR-1) (Leukocyte LILRB1 ILT2 LIR1 650 immunoglobulin-like receptor 1) (CD85 antigen-like family member J) (Immunoglobulin- MIR7 like transcript 2) (ILT-2) (Monocyte/macrophage immunoglobulin-like receptor 7) (MIR-7) (CD antigen CD85j) Q96QE4 LR37B_HUMAN Leucine-rich repeat-containing protein 37B (C66 SLIT-like testicular protein) LRRC37B 947 Q9HCJ2 LRC4C_HUMAN Leucine-rich repeat-containing protein 4C (Netrin-G1 ligand) (NGL-1) LRRC4C KIAA1580 640 NGL1 UNQ292/PRO331 Q9P2V4 LRIT1_HUMAN Leucine-rich repeat, immunoglobulin-like domain and transmembrane domain-containing LRIT1 LRRC21 PAL 623 protein 1 (Leucine-rich repeat-containing protein 21) (Photoreceptor-associated LRR superfamily protein) (Retina-specific protein PAL) P29376 LTK_HUMAN Leukocyte tyrosine kinase receptor (EC 2.7.10.1) (Protein tyrosine kinase 1) LTK TYK1 864 Q9HBG7 LY9_HUMAN T-lymphocyte surface antigen Ly-9 (Cell surface molecule Ly-9) (Lymphocyte antigen 9) LY9 CDABP0070 655 (SLAM family member 3) (SLAMF3) (Signaling lymphocytic activation molecule 3) (CD antigen CD229) P14151 LYAM1_HUMAN L-selectin (CD62 antigen-like family member L) (Leukocyte adhesion molecule 1) (LAM-1) SELL LNHR LYAM1 372 (Leukocyte surface antigen Leu-8) (Leukocyte-endothelial cell adhesion molecule 1) (LECAM1) (Lymph node homing receptor) (TQ1) (gp90-MEL) (CD antigen CD62L) Q5SZI1 LRAD2_HUMAN Low-density lipoprotein receptor class A domain-containing protein 2 LDLRAD2 272 Q8TF66 LRC15_HUMAN Leucine-rich repeat-containing protein 15 (Leucine-rich repeat protein induced by beta- LRRC15 LIB 581 amyloid homolog) (hLib) Q2I0M4 LRC26_HUMAN Leucine-rich repeat-containing protein 26 (BK channel auxiliary gamma subunit LRRC26) LRRC26 CAPC 334 (Cytokeratin-associated protein in cancer) Q9P244 LRFN1_HUMAN Leucine-rich repeat and fibronectin type III domain-containing protein 1 (Synaptic LRFN1 KIAA1484 771 adhesion-like molecule 2) SALM2 Q9ULH4 LRFN2_HUMAN Leucine-rich repeat and fibronectin type-III domain-containing protein 2 (Synaptic LRFN2 KIAA1246 789 adhesion-like molecule 1) SALM1 Q9BTN0 LRFN3_HUMAN Leucine-rich repeat and fibronectin type-III domain-containing protein 3 (Synaptic LRFN3 SALM4 628 adhesion-like molecule 4) UNQ5865/PRO34192 Q6PJG9 LRFN4_HUMAN Leucine-rich repeat and fibronectin type-III domain-containing protein 4 LRFN4 SALM3 635 Q96NI6 LRFN5_HUMAN Leucine-rich repeat and fibronectin type-III domain-containing protein 5 LRFN5 C14orf146 719 SALM5 Q96JA1 LRIG1_HUMAN Leucine-rich repeats and immunoglobulin-like domains protein 1 (LIG-1) LRIG1 LIG1 1093 O94898 LRIG2_HUMAN Leucine-rich repeats and immunoglobulin-like domains protein 2 (LIG-2) LRIG2 KIAA0806 1065 LIG2 Q6UXM1 LRIG3_HUMAN Leucine-rich repeats and immunoglobulin-like domains protein 3 (LIG-3) LRIG3 LIG3 1119 UNQ287/PRO326/ PRO335 Q9HBW1 LRRC4_HUMAN Leucine-rich repeat-containing protein 4 (Brain tumor-associated protein BAG) LRRC4 BAG 653 (Nasopharyngeal carcinoma-associated gene 14 protein) (Netrin-G2 ligand) (NGL-2) NAG14 UNQ554/PRO1111 Q6UXK5 LRRN1_HUMAN Leucine-rich repeat neuronal protein 1 (Neuronal leucine-rich repeat protein 1) (NLRR-1) LRRN1 KIAA1497 716 Nbla10449 UNQ693/PRO1338 Q86VH5 LRRT3_HUMAN Leucine-rich repeat transmembrane neuronal protein 3 LRRTM3 581 UNQ803/PRO1693 P16581 LYAM2_HUMAN E-selectin (CD62 antigen-like family member E) (Endothelial leukocyte adhesion SELE ELAM1 610 molecule 1) (ELAM-1) (Leukocyte-endothelial cell adhesion molecule 2) (LECAM2) (CD antigen CD62E) P16109 LYAM3_HUMAN P-selectin (CD62 antigen-like family member P) (Granule membrane protein 140) (GMP- SELP GMRP GRMP 830 140) (Leukocyte-endothelial cell adhesion molecule 3) (LECAM3) (Platelet activation dependent granule-external membrane protein) (PADGEM) (CD antigen CD62P) O75019 LIRA1_HUMAN Leukocyte immunoglobulin-like receptor subfamily A member 1 (CD85 antigen-like family LILRA1 LIR6 489 member I) (Leukocyte immunoglobulin-like receptor 6) (LIR-6) (CD antigen CD85i) Q8NHJ6 LIRB4_HUMAN Leukocyte immunoglobulin-like receptor subfamily B member 4 (CD85 antigen-like family LILRB4 ILT3 LIR5 448 member K) (Immunoglobulin-like transcript 3) (ILT-3) (Leukocyte immunoglobulin-like receptor 5) (LIR-5) (Monocyte inhibitory receptor HM18) (CD antigen CD85k) Q6ZMQ8 LMTK1_HUMAN Serine/threonine-protein kinase LMTK1 (EC 2.7.11.1) (Apoptosis-associated tyrosine AATK AATYK 1374 kinase) (AATYK) (Brain apoptosis-associated tyrosine kinase) (CDK5-binding protein) KIAA0641 LMR1 (Lemur tyrosine kinase 1) (p35-binding protein) (p35BP) LMTK1 Q8N386 LRC25_HUMAN Leucine-rich repeat-containing protein 25 (Monocyte and plasmacytoid-activated protein) LRRC25 MAPA 305 UNQ6169/PRO20174 Q8ND94 LRN4L_HUMAN LRRN4 C-terminal-like protein LRRN4CL 238 UNQ728/PRO1410 Q86VZ4 LRP11_HUMAN Low-density lipoprotein receptor-related protein 11 (LRP-11) LRP11 500 Q07954 LRP1_HUMAN Prolow-density lipoprotein receptor-related protein 1 (LRP-1) (Alpha-2-macroglobulin LRP1 A2MR APR 4544 receptor) (A2MR) (Apolipoprotein E receptor) (APOER) (CD antigen CD91) [Cleaved into: Low-density lipoprotein receptor-related protein 1 85 kDa subunit (LRP-85); Low-density lipoprotein receptor-related protein 1 515 kDa subunit (LRP-515); Low-density lipoprotein receptor-related protein 1 intracellular domain (LRPICD)] O75074 LRP3_HUMAN Low-density lipoprotein receptor-related protein 3 (LRP-3) (105 kDa low-density LRP3 770 lipoprotein receptor-related protein) (hLRp105) O75096 LRP4_HUMAN Low-density lipoprotein receptor-related protein 4 (LRP-4) (Multiple epidermal growth LRP4 KIAA0816 1905 factor-like domains 7) LRP10 MEGF7 Q14114 LRP8_HUMAN Low-density lipoprotein receptor-related protein 8 (LRP-8) (Apolipoprotein E receptor 2) LRP8 APOER2 963 O43300 LRRT2_HUMAN Leucine-rich repeat transmembrane neuronal protein 2 (Leucine-rich repeat neuronal 2 LRRTM2 KIAA0416 516 protein) LRRN2 Q9HBL6 LRTM1_HUMAN Leucine-rich repeat and transmembrane domain-containing protein 1 LRTM1 HT017 345 Q7Z4F1 LRP10_HUMAN Low-density lipoprotein receptor-related protein 10 (LRP-10) LRP10 MSTP087 713 SP220 UNQ389/PRO724 Q8N967 LRTM2_HUMAN Leucine-rich repeat and transmembrane domain-containing protein 2 LRTM2 370 Q9Y561 LRP12_HUMAN Low-density lipoprotein receptor-related protein 12 (LRP-12) (Suppressor of LRP12 ST7 859 tumorigenicity 7 protein) P98164 LRP2_HUMAN Low-density lipoprotein receptor-related protein 2 (LRP-2) (Glycoprotein 330) (gp330) LRP2 4655 (Megalin) Q9H8J5 MANS1_HUMAN MANSC domain-containing protein 1 (Loss of heterozygosity 12 chromosomal region 3 MANSC1 431 protein) LOH12CR3 UNQ316/PRO361 Q86YD5 LRAD3_HUMAN Low-density lipoprotein receptor class A domain-containing protein 3 LDLRAD3 345 Q14392 LRC32_HUMAN Leucine-rich repeat-containing protein 32 (Garpin) (Glycoprotein A repetitions LRRC32 D11S833E 662 predominant) (GARP) GARP Q9NZR2 LRP1B_HUMAN Low-density lipoprotein receptor-related protein 1B (LRP-1B) (Low-density lipoprotein LRP1B LRPDIT 4599 receptor-related protein-deleted in tumor) (LRP-DIT) O75325 LRRN2_HUMAN Leucine-rich repeat neuronal protein 2 (Glioma amplified on chromosome 1 protein) LRRN2 GAC1 713 (Leucine-rich repeat neuronal protein 5) LRRN5 UNQ256/PRO293 Q8WUT4 LRRN4_HUMAN Leucine-rich repeat neuronal protein 4 (Neuronal leucine-rich repeat protein 4) (NLRR-4) LRRN4 C20orf75 740 Q86UE6 LRRT1_HUMAN Leucine-rich repeat transmembrane neuronal protein 1 LRRTM1 522 UNQ675/PRO1309 A6NHS7 MANS4_HUMAN MANSC domain-containing protein 4 MANSC4 340 P15529 MCP_HUMAN Membrane cofactor protein (TLX) (Trophoblast leukocyte common antigen) (CD antigen CD46 MCP MIC10 392 CD46) Q86VH4 LRRT4_HUMAN Leucine-rich repeat transmembrane neuronal protein 4 LRRTM4 590 UNQ3075/PRO9907 Q13477 MADCA_HUMAN Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) (hMAdCAM-1) MADCAM1 382 Q5SQ64 LY66F_HUMAN Lymphocyte antigen 6 complex locus protein G6f LY6G6F C6orf21 297 G6F LY6G6D NG32 O60449 LY75_HUMAN Lymphocyte antigen 75 (Ly-75) (C-type lectin domain family 13 member B) (DEC-205) LY75 CD205 1722 (gp200-MR6) (CD antigen CD205) CLEC13B Q9Y5Y7 LYVE1_HUMAN Lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1) (Cell surface retention LYVE1 CRSBP1 322 sequence-binding protein 1) (CRSBP-1) (Extracellular link domain-containing protein 1) HAR XLKD1 (Hyaluronic acid receptor) UNQ230/PRO263 P20916 MAG_HUMAN Myelin-associated glycoprotein (Siglec-4a) MAG GMA 626 Q16820 MEP1B_HUMAN Meprin A subunit beta (EC 3.4.24.63) (Endopeptidase-2) (Meprin B) (N-benzoyl-L-tyrosyl- MEP1B 701 P-amino-benzoic acid hydrolase subunit beta) (PABA peptide hydrolase) (PPH beta) Q9H9K5 MER34_HUMAN Endogenous retrovirus group MER34 member 1 Env polyprotein (HERV-MER_4q12 ERVMER34-1 563 provirus ancestral Env polyprotein) LP9056 Q14703 MBTP1_HUMAN Membrane-bound transcription factor site-1 protease (EC 3.4.21.112) (Endopeptidase MBTPS1 KIAA0091 1052 S1P) (Subtilisin/kexin-isozyme 1) (SKI-1) S1P SKI1 Q12866 MERTK_HUMAN Tyrosine-protein kinase Mer (EC 2.7.10.1) (Proto-oncogene c-Mer) (Receptor tyrosine MERTK MER 999 kinase MerTK) Q7Z7M0 MEGF8_HUMAN Multiple epidermal growth factor-like domains protein 8 (Multiple EGF-like domains MEGF8 C19orf49 2845 protein 8) (Epidermal growth factor-like protein 4) (EGF-like protein 4) EGFL4 KIAA0817 P55082 MFAP3_HUMAN Microfibril-associated glycoprotein 3 MFAP3 362 Q96KG7 MEG10_HUMAN Multiple epidermal growth factor-like domains protein 10 (Multiple EGF-like domains MEGF10 KIAA1780 1140 protein 10) A6BM72 MEG11_HUMAN Multiple epidermal growth factor-like domains protein 11 (Multiple EGF-like domains MEGF11 KIAA1781 1044 protein 11) UNQ1949/PRO4432 Q16819 MEP1A_HUMAN Meprin A subunit alpha (EC 3.4.24.18) (Endopeptidase-2) (N-benzoyl-L-tyrosyl-P-amino- MEP1A 746 benzoic acid hydrolase subunit alpha) (PABA peptide hydrolase) (PPH alpha) P51512 MMP16_HUMAN Matrix metalloproteinase-16 (MMP-16) (EC 3.4.24.—) (MMP-X2) (Membrane-type matrix MMP16 MMPX2 607 metalloproteinase 3) (MT-MMP 3) (MTMMP3) (Membrane-type-3 matrix metalloproteinase) (MT3-MMP) (MT3MMP) Q9H1U4 MEGF9_HUMAN Multiple epidermal growth factor-like domains protein 9 (Multiple EGF-like domains MEGF9 EGFL5 602 protein 9) (Epidermal growth factor-like protein 5) (EGF-like protein 5) KIAA0818 UNQ671/PRO1305 Q5JRA6 MIA3_HUMAN Melanoma inhibitory activity protein 3 (C219-reactive peptide) (D320) (Transport and MIA3 KIAA0268 1907 Golgi organization protein 1) TANGO TANGO1 UNQ6077/PRO20088 P51511 MMP15_HUMAN Matrix metalloproteinase-15 (MMP-15) (EC 3.4.24.—) (Membrane-type matrix MMP15 669 metalloproteinase 2) (MT-MMP 2) (MTMMP2) (Membrane-type-2 matrix metalloproteinase) (MT2-MMP) (MT2MMP) (SMCP-2) O75121 MFA3L_HUMAN Microfi brillar-associated protein 3-like (Testis development protein NYD-SP9) MFAP3L KIAA0626 409 HSD-39 HSD39 P08581 MET_HUMAN Hepatocyte growth factor receptor (HGF receptor) (EC 2.7.10.1) (HGF/SF receptor) MET 1390 (Proto-oncogene c-Met) (Scatter factor receptor) (SF receptor) (Tyrosine-protein kinase Met) Q29983 MICA_HUMAN MHC class I polypeptide-related sequence A (MIC-A) MICA PERB11.1 383 Q8TD46 MO2R1_HUMAN Cell surface glycoprotein CD200 receptor 1 (CD200 cell surface glycoprotein receptor) CD200R1 CD200R 325 (Cell surface glycoprotein OX2 receptor 1) CRTR2 MOX2R OX2R UNQ2522/PRO6015 Q29980 MICB_HUMAN MHC class I polypeptide-related sequence B (MIC-B) MICB PERB11.2 383 P50281 MMP14_HUMAN Matrix metalloproteinase-14 (MMP-14) (EC 3.4.24.80) (MMP-X1) (Membrane-type matrix MMP14 582 metalloproteinase 1) (MT-MMP 1) (MTMMP1) (Membrane-type-1 matrix metalloproteinase) (MT1-MMP) (MT1MMP) Q2M385 MPEG1_HUMAN Macrophage-expressed gene 1 protein (Macrophage gene 1 protein) (Mpg-1) MPEG1 716 Q7Z6M3 MILR1_HUMAN Allergin-1 (Allergy inhibitory receptor 1) (Mast cell antigen 32) (MCA-32) (Mast cell MILR1 C17orf60 343 immunoglobulin-like receptor 1) MCA32 P20645 MPRD_HUMAN Cation-dependent mannose-6-phosphate receptor (CD Man-6-P receptor) (CD-MPR) (46 M6PR MPR46 277 kDa mannose 6-phosphate receptor) (MPR 46) MPRD P11717 MPRI_HUMAN Cation-independent mannose-6-phosphate receptor (CI Man-6-P receptor) (CI-MPR) IGF2R MPRI 2491 (M6PR) (300 kDa mannose 6-phosphate receptor) (MPR 300) (Insulin-like growth factor 2 receptor) (Insulin-like growth factor II receptor) (IGF-II receptor) (M6P/IGF2 receptor) (M6P/IGF2R) (CD antigen CD222) Q14165 MLEC_HUMAN Malectin MLEC KIAA0152 292 Q9Y5R2 MMP24_HUMAN Matrix metalloproteinase-24 (MMP-24) (EC 3.4.24.—) (Membrane-type matrix MMP24 MT5MMP 645 metalloproteinase 5) (MT-MMP 5) (MTMMP5) (Membrane-type-5 matrix metalloproteinase) (MT5-MMP) (MT5MMP) [Cleaved into: Processed matrix metalloproteinase-24] Q16653 MOG_HUMAN Myelin-oligodendrocyte glycoprotein MOG 247 Q6UWV2 MPZL3_HUMAN Myelin protein zero-like protein 3 MPZL3 235 UNQ2966/PRO7425 Q6UVY6 MOXD1_HUMAN DBH-like monooxygenase protein 1 (EC 1.14.17.—) (Monooxygenase X) MOXD1 MOX 613 UNQ2493/PRO5780 Q6Q8B3 MO2R2_HUMAN Cell surface glycoprotein CD200 receptor 2 (CD200 cell surface glycoprotein receptor-like CD200R1L 271 2) (CD200 receptor-like 2) (HuCD200R2) (CD200 cell surface glycoprotein receptor-like CD200R2 a) (CD200RLa) (Cell surface glycoprotein CD200 receptor 1-like) (Cell surface glycoprotein OX2 receptor 2) O60487 MPZL2_HUMAN Myelin protein zero-like protein 2 (Epithelial V-like antigen 1) MPZL2 EVA EVA1 215 UNQ606/PRO1192 Q96KJ4 MSLNL_HUMAN Mesothelin-like protein (Pre-pro-megakaryocyte-potentiating-factor-like) MSLNL C16orf37 702 MPFL P43121 MUC18_HUMAN Cell surface glycoprotein MUC18 (Cell surface glycoprotein P1H12) (Melanoma cell MCAM MUC18 646 adhesion molecule) (Melanoma-associated antigen A32) (Melanoma-associated antigen MUC18) (S-endo 1 endothelial-associated antigen) (CD antigen CD146) P15941 MUC1_HUMAN Mucin-1 (MUC-1) (Breast carcinoma-associated antigen DF3) (Cancer antigen 15-3) (CA MUC1 PUM 1255 15-3) (Carcinoma-associated mucin) (Episialin) (H23AG) (Krebs von den Lungen-6) (KL- 6) (PEMT) (Peanut-reactive urinary mucin) (PUM) (Polymorphic epithelial mucin) (PEM) (Tumor-associated epithelial membrane antigen) (EMA) (Tumor-associated mucin) (CD antigen CD227) [Cleaved into: Mucin-1 subunit alpha (MUC1-NT) (MUC1-alpha); Mucin-1 subunit beta (MUC1-beta) (MUC1-CT)] O95297 MPZL1_HUMAN Myelin protein zero-like protein 1 (Protein zero-related) MPZL1 PZR 269 UNQ849/PRO1787 P22897 MRC1_HUMAN Macrophage mannose receptor 1 (MMR) (C-type lectin domain family 13 member D) (C- MRC1 CLEC13D 1456 type lectin domain family 13 member D-like) (Human mannose receptor) (hMR) CLEC13DL (Macrophage mannose receptor 1-like protein 1) (CD antigen CD206) MRC1L1 Q9UBG0 MRC2_HUMAN C-type mannose receptor 2 (C-type lectin domain family 13 member E) (Endocytic MRC2 CLEC13E 1479 receptor 180) (Macrophage mannose receptor 2) (Urokinase-type plasminogen activator ENDO180 receptor-associated protein) (UPAR-associated protein) (Urokinase receptor-associated KIAA0709 UPARAP protein) (CD antigen CD280) Q9UKN1 MUC12_HUMAN Mucin-12 (MUC-12) (Mucin-11) (MUC-11) MUC12 MUC11 5478 Q8N387 MUC15_HUMAN Mucin-15 (MUC-15) MUC15 334 UNQ750/PRO1481 Q8WXI7 MUC16_HUMAN Mucin-16 (MUC-16) (Ovarian cancer-related tumor marker CA125) (CA-125) (Ovarian MUC16 CA125 14507 carcinoma antigen CA125) Q5SSG8 MUC21_HUMAN Mucin-21 (MUC-21) (Epiglycanin) MUC21 C6orf205 566 UNQ697/PRO1342 Q9H3R2 MUC13_HUMAN Mucin-13 (MUC-13) (Down-regulated in colon cancer 1) MUC13 DRCC1 512 RECC UNQ6194/PRO20221 O15146 MUSK_HUMAN Muscle, skeletal receptor tyrosine-protein kinase (EC 2.7.10.1) (Muscle-specific tyrosine- MUSK 869 protein kinase receptor) (MuSK) (Muscle-specific kinase receptor) Q13505 MTX1_HUMAN Metaxin-1 (Mitochondrial outer membrane import complex protein 1) MTX1 MTX MTXN 466 Q9ULC0 MUCEN_HUMAN Endomucin (Endomucin-2) (Gastric cancer antigen Ga34) (Mucin-14) (MUC-14) EMCN EMCN2 261 MUC14 Q04900 MUC24_HUMAN Sialomucin core protein 24 (MUC-24) (Endolyn) (Multi-glycosylated core protein 24) CD164 197 (MGC-24) (MGC-24v) (CD antigen CD164) P25189 MYP0_HUMAN Myelin protein P0 (Myelin peripheral protein) (MPP) (Myelin protein zero) MPZ 248 Q9BRK3 MXRA8_HUMAN Matrix-remodeling-associated protein 8 (Limitrin) MXRA8 442 Q9UK23 NAGPA_HUMAN N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (EC 3.1.4.45) NAGPA 515 (Mannose 6-phosphate-uncovering enzyme) (Phosphodiester alpha-GlcNAcase) O15394 NCAM2_HUMAN Neural cell adhesion molecule 2 (N-CAM-2) (NCAM-2) NCAM2 NCAM21 837 O76036 NCTR1_HUMAN Natural cytotoxicity triggering receptor 1 (Lymphocyte antigen 94 homolog) (NK cell- NCR1 LY94 304 activating receptor) (Natural killer cell p46-related protein) (NK-p46) (NKp46) (hNKp46) (CD antigen CD335) Q8NC67 NETO2_HUMAN Neuropilin and tolloid-like protein 2 (Brain-specific transmembrane protein containing 2 NETO2 BTCL2 525 CUB and 1 LDL-receptor class A domains protein 2) UNQ1926/PRO4401 Q8TD07 N2DL4_HUMAN NKG2D ligand 4 (N2DL-4) (NKG2DL4) (Lymphocyte effector toxicity activation ligand) RAET1E LETAL 263 (RAE-1-like transcript 4) (RL-4) (Retinoic acid early transcript 1E) N2DL4 ULBP4 UNQ1867/PRO4303 O14931 NCTR3_HUMAN Natural cytotoxicity triggering receptor 3 (Activating natural killer receptor p30) (Natural NCR3 1C7 LY117 201 killer cell p30-related protein) (NK-p30) (NKp30) (CD antigen CD337) Q8TDF5 NETO1_HUMAN Neuropilin and tolloid-like protein 1 (Brain-specific transmembrane protein containing 2 NETO1 BTCL1 533 CUB and 1 LDL-receptor class A domains protein 1) Q92542 NICA_HUMAN Nicastrin NCSTN KIAA0253 709 UNQ1874/PRO4317 P13591 NCAM1_HUMAN Neural cell adhesion molecule 1 (N-CAM-1) (NCAM-1) (CD antigen CD56) NCAM1 NCAM 858 Q5T1S8 NCMAP_HUMAN Noncompact myelin-associated protein (Myelin protein of 11 kDa) (MP11) NCMAP C1orf130 102 O95944 NCTR2_HUMAN Natural cytotoxicity triggering receptor 2 (Lymphocyte antigen 95 homolog) (NK cell- NCR2 LY95 276 activating receptor) (Natural killer cell p44-related protein) (NK-p44) (NKp44) (CD antigen CD336) Q15223 NECT1_HUMAN Nectin-1 (Herpes virus entry mediator C) (Herpesvirus entry mediator C) (HveC) NECTIN1 HVEC 517 (Herpesvirus Ig-like receptor) (HIgR) (Nectin cell adhesion molecule 1) (Poliovirus PRR1 PVRL1 receptor-related protein 1) (CD antigen CD111) Q92859 NEO1_HUMAN Neogenin (Immunoglobulin superfamily DCC subclass member 2) NEO1 IGDCC2 1461 NGN O00533 NCHL1_HUMAN Neural cell adhesion molecule L1-like protein (Close homolog of L1) [Cleaved into: CHL1 CALL 1208 Processed neural cell adhesion molecule L1-like protein] Q8N2Q7 NLGN1_HUMAN Neuroligin-1 NLGN1 KIAA1070 840 Q8N0W4 NLGNX_HUMAN Neuroligin-4, X-linked (Neuroligin X) (HNLX) NLGN4X KIAA1260 816 NLGN4 UNQ365/PRO701 O60500 NPHN_HUMAN Nephrin (Renal glomerulus-specific cell adhesion receptor) NPHS1 NPHN 1241 Q96NY8 NECT4_HUMAN Nectin-4 (Ig superfamily receptor LNIR) (Nectin cell adhesion molecule 4) (Poliovirus NECTIN4 LNIR 510 receptor-related protein 4) [Cleaved into: Processed poliovirus receptor-related protein 4] PRR4 PVRL4 Q8NET5 NFAM1_HUMAN NFAT activation molecule 1 (Calcineurin/NFAT-activating ITAM-containing protein) NFAM1 CNAIP 270 (NFAT-activating protein with ITAM motif 1) O94856 NFASC_HUMAN Neurofascin NFASC KIAA0756 1347 Q9UM47 NOTC3_HUMAN Neurogenic locus notch homolog protein 3 (Notch 3) [Cleaved into: Notch 3 extracellular NOTCH3 2321 truncation; Notch 3 intracellular domain] O14511 NRG2_HUMAN Pro-neuregulin-2, membrane-bound isoform (Pro-NRG2) [Cleaved into: Neuregulin-2 NRG2 NTAK 850 (NRG-2) (Divergent of neuregulin-1) (DON-1) (Neural- and thymus-derived activator for ERBB kinases) (NTAK)] Q02297 NRG1_HUMAN Pro-neuregulin-1, membrane-bound isoform (Pro-NRG1) [Cleaved into: Neuregulin-1 NRG1 GGF HGL 640 (Acetylcholine receptor-inducing activity) (ARIA) (Breast cancer cell differentiation factor HRGA NDF SMDF p45) (Glial growth factor) (Heregulin) (HRG) (Neu differentiation factor) (Sensory and motor neuron-derived factor)] Q9Y4C0 NRX3A_HUMAN Neurexin-3 (Neurexin III-alpha) (Neurexin-3-alpha) NRXN3 C14orf60 1643 KIAA0743 Q92692 NECT2_HUMAN Nectin-2 (Herpes virus entry mediator B) (Herpesvirus entry mediator B) (HveB) (Nectin NECTIN2 HVEB 538 cell adhesion molecule 2) (Poliovirus receptor-related protein 2) (CD antigen CD112) PRR2 PVRL2 Q8NFZ4 NLGN2_HUMAN Neuroligin-2 NLGN2 KIAA1366 835 Q8NFZ3 NLGNY_HUMAN Neuroligin-4, Y-linked (Neuroligin Y) NLGN4Y KIAA0951 816 Q15155 NOMO1_HUMAN Nodal modulator 1 (pM5 protein) NOMO1 PM5 1222 P69849 NOMO3_HUMAN Nodal modulator 3 (pM5 protein 3) NOMO3 1222 Q9NZ94 NLGN3_HUMAN Neuroligin-3 (Gliotactin homolog) NLGN3 KIAA1480 848 NL3 P46531 NOTC1_HUMAN Neurogenic locus notch homolog protein 1 (Notch 1) (hN1) (Translocation-associated NOTCH1 TAN1 2555 notch protein TAN-1) [Cleaved into: Notch 1 extracellular truncation (NEXT); Notch 1 intracellular domain (NICD)] Q04721 NOTC2_HUMAN Neurogenic locus notch homolog protein 2 (Notch 2) (hN2) [Cleaved into: Notch 2 NOTCH2 2471 extracellular truncation (N2ECD); Notch 2 intracellular domain (N2ICD)] Q92823 NRCAM_HUMAN Neuronal cell adhesion molecule (Nr-CAM) (Neuronal surface protein Bravo) (hBravo) NRCAM KIAA0343 1304 (NgCAM-related cell adhesion molecule) (Ng-CAM-related) O60462 NRP2_HUMAN Neuropilin-2 (Vascular endothelial cell growth factor 165 receptor 2) NRP2 VEGF165R2 931 Q9Y639 NPTN_HUMAN Neuroplastin (Stromal cell-derived receptor 1) (SDR-1) NPTN SDFR1 398 SDR1 Q68D85 NR3L1_HUMAN Natural cytotoxicity triggering receptor 3 ligand 1 (B7 homolog 6) (B7-H6) NCR3LG1 B7H6 454 O14786 NRP1_HUMAN Neuropilin-1 (Vascular endothelial cell growth factor 165 receptor) (CD antigen CD304) NRP1 NRP 923 VEGF165R P56975 NRG3_HUMAN Pro-neuregulin-3, membrane-bound isoform (Pro-NRG3) [Cleaved into: Neuregulin-3 NRG3 720 (NRG-3)] Q86YC3 NRROS_HUMAN Negative regulator of reactive oxygen species (Leucine-rich repeat-containing protein 33) NRROS LRRC33 692 UNQ3030/PRO9833 P58400 NRX1B_HUMAN Neurexin-1-beta (Neurexin 1-beta) NRXN1 442 Q9HDB5 NRX3B_HUMAN Neurexin-3-beta (Neurexin III-beta) [Cleaved into: Neurexin-3-beta, soluble form; NRXN3 KIAA0743 637 Neurexin-3-beta, C-terminal fragment (NRXN3-CTF)] Q16620 NTRK2_HUMAN BDNF/NT-3 growth factors receptor (EC 2.7.10.1) (GP145-TrkB) (Trk-B) (Neurotrophic NTRK2 TRKB 822 tyrosine kinase receptor type 2) (TrkB tyrosine kinase) (Tropomyosin-related kinase B) Q16288 NTRK3_HUMAN NT-3 growth factor receptor (EC 2.7.10.1) (GP145-TrkC) (Trk-C) (Neurotrophic tyrosine NTRK3 TRKC 839 kinase receptor type 3) (TrkC tyrosine kinase) Q99466 NOTC4_HUMAN Neurogenic locus notch homolog protein 4 (Notch 4) (hNotch4) [Cleaved into: Notch 4 NOTCH4 INT3 2003 extracellular truncation; Notch 4 intracellular domain] Q8WWG1 NRG4_HUMAN Pro-neuregulin-4, membrane-bound isoform (Pro-NRG4) [Cleaved into: Neuregulin-4 NRG4 115 (NRG-4)] Q9P2S2 NRX2A_HUMAN Neurexin-2 (Neurexin II-alpha) (Neurexin-2-alpha) NRXN2 KIAA0921 1712 Q9ULB1 NRX1A_HUMAN Neurexin-1 (Neurexin I-alpha) (Neurexin-1-alpha) NRXN1 KIAA0578 1477 P58401 NRX2B_HUMAN Neurexin-2-beta (Neurexin II-beta) NRXN2 666 P04629 NTRK1_HUMAN High affinity nerve growth factor receptor (EC 2.7.10.1) (Neurotrophic tyrosine kinase NTRK1 MTC TRK 796 receptor type 1) (TRK1-transforming tyrosine kinase protein) (Tropomyosin-related kinase TRKA A) (Tyrosine kinase receptor) (Tyrosine kinase receptor A) (Trk-A) (gp140trk) (p140-TrkA) Q96PE5 OPALI_HUMAN Opalin (Oligodendrocytic myelin paranodal and inner loop protein) (Transmembrane OPALIN HTMP10 141 protein 10) TMEM10 P41217 OX2G_HUMAN OX-2 membrane glycoprotein (CD antigen CD200) CD200 MOX1 278 MOX2 My033 Q8NBR0 P5I13_HUMAN Tumor protein p53-inducible protein 13 (Damage-stimulated cytoplasmic protein 1) TP53I13 DSCP1 393 Q99650 OSMR_HUMAN Oncostatin-M-specific receptor subunit beta (Interleukin-31 receptor subunit beta) (IL-31 OSMR OSMRB 979 receptor subunit beta) (IL-31R subunit beta) (IL-31R-beta) (IL-31RB) Q8IYS5 OSCAR_HUMAN Osteoclast-associated immunoglobulin-like receptor (Osteoclast-associated receptor) OSCAR 282 (hOSCAR) (Polymeric immunoglobulin receptor 3) (PIgR-3) (PIgR3) (Poly-Ig receptor 3) P39656 OST48_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST DDOST KIAA0115 456 48 kDa subunit) (Oligosaccharyl transferase 48 kDa subunit) (EC 2.4.99.18) OST48 OK/SW- cl.45 Q86WC4 OSTM1_HUMAN Osteopetrosis-associated transmembrane protein 1 (Chloride channel 7 beta subunit) OSTM1 GL 334 HSPC019 UNQ6098/PRO21201 Q9BZA7 PC11X_HUMAN Protocadherin-11 X-linked (Protocadherin-11) (Protocadherin on the X chromosome) PCDH11X 1347 (PCDH-X) (Protocadherin-S) KIAA1326 PCDH11 PCDHX Q9P2E7 PCD10_HUMAN Protocadherin-10 PCDH10 KIAA1400 1040 Q96QU1 PCD15_HUMAN Protocadherin-15 PCDH15 USH1F 1955 Q8N6Y1 PCD20_HUMAN Protocadherin-20 (Protocadherin-13) PCDH20 PCDH13 951 Q9UN67 PCDBA_HUMAN Protocadherin beta-10 (PCDH-beta-10) PCDHB10 800 UNQ1906/PRO4352 Q9Y5E8 PCDBF_HUMAN Protocadherin beta-15 (PCDH-beta-15) PCDHB15 787 Q9Y5I4 PCDC2_HUMAN Protocadherin alpha-C2 (PCDH-alpha-C2) PCDHAC2 1007 Q9Y5H0 PCDG3_HUMAN Protocadherin gamma-A3 (PCDH-gamma-A3) PCDHGA3 932 Q9Y5G8 PCDG5_HUMAN Protocadherin gamma-A5 (PCDH-gamma-A5) PCDHGA5 931 Q9Y5G6 PCDG7_HUMAN Protocadherin gamma-A7 (PCDH-gamma-A7) PCDHGA7 932 Q9Y5G1 PCDGF_HUMAN Protocadherin gamma-B3 (PCDH-gamma-B3) PCDHGB3 929 Q96FE7 P3IP1_HUMAN Phosphoinositide-3-kinase-interacting protein 1 (Kringle domain-containing protein HGFL) PIK3IP1 HGFL 263 Q9HCL0 PCD18_HUMAN Protocadherin-18 PCDH18 KIAA1562 1135 Q9Y5H7 PCDA5_HUMAN Protocadherin alpha-5 (PCDH-alpha-5) PCDHA5 CNRS6 936 Q9Y5I1 PCDAB_HUMAN Protocadherin alpha-11 (PCDH-alpha-11) PCDHA11 CNRS7 949 Q9Y5E7 PCDB2_HUMAN Protocadherin beta-2 (PCDH-beta-2) PCDHB2 798 Q9Y5E5 PCDB4_HUMAN Protocadherin beta-4 (PCDH-beta-4) PCDHB4 795 Q9HC56 PCDH9_HUMAN Protocadherin-9 PCDH9 1237 Q92824 PCSK5_HUMAN Proprotein convertase subtilisin/kexin type 5 (EC 3.4.21.—) (Proprotein convertase 5) PCSK5 PC5 PC6 1860 (PC5) (Proprotein convertase 6) (PC6) (hPC6) (Subtilisin/kexin-like protease PC5) Q96JQ0 PCD16_HUMAN Protocadherin-16 (Cadherin-19) (Cadherin-25) (Fibroblast cadherin-1) (Protein dachsous DCHS1 CDH19 3298 homolog 1) CDH25 FIB1 KIAA1773 PCDH16 Q9Y5I0 PCDAD_HUMAN Protocadherin alpha-13 (PCDH-alpha-13) PCDHA13 CNRS5 950 Q9Y5E6 PCDB3_HUMAN Protocadherin beta-3 (PCDH-beta-3) PCDHB3 796 Q9Y5E3 PCDB6_HUMAN Protocadherin beta-6 (PCDH-beta-6) PCDHB6 794 Q9Y5F1 PCDBC_HUMAN Protocadherin beta-12 (PCDH-beta-12) PCDHB12 795 Q9Y5G7 PCDG6_HUMAN Protocadherin gamma-A6 (PCDH-gamma-A6) PCDHGA6 932 Q9Y5G5 PCDG8_HUMAN Protocadherin gamma-A8 (PCDH-gamma-A8) PCDHGA8 932 KIAA0327 Q9Y5H3 PCDGA_HUMAN Protocadherin gamma-A10 (PCDH-gamma-A10) PCDHGA10 936 Q9Y5H2 PCDGB_HUMAN Protocadherin gamma-A11 (PCDH-gamma-A11) PCDHGA11 935 Q9Y5F6 PCDGM_HUMAN Protocadherin gamma-C5 (PCDH-gamma-C5) PCDHGC5 944 Q08174 PCDH1_HUMAN Protocadherin-1 (Cadherin-like protein 1) (Protocadherin-42) (PC42) PCDH1 1060 O95206 PCDH8_HUMAN Protocadherin-8 (Arcadlin) PCDH8 1070 Q9NZQ7 PD1L1_HUMAN Programmed cell death 1 ligand 1 (PD-L1) (PDCD1 ligand 1) (Programmed death ligand CD274 B7H1 290 1) (B7 homolog 1) (B7-H1) (CD antigen CD274) PDCD1L1 PDCD1LG1 PDL1 Q6UWI2 PARM1_HUMAN Prostate androgen-regulated mucin-like protein 1 (PARM-1) PARM1 310 UNQ1879/PRO4322 Q9Y5I3 PCDA1_HUMAN Protocadherin alpha-1 (PCDH-alpha-1) PCDHA1 950 Q9Y5H8 PCDA3_HUMAN Protocadherin alpha-3 (PCDH-alpha-3) PCDHA3 950 Q9UN74 PCDA4_HUMAN Protocadherin alpha-4 (PCDH-alpha-4) PCDHA4 947 Q86YL7 PDPN_HUMAN Podoplanin (Aggrus) (Glycoprotein 36) (Gp36) (PA2.26 antigen) (T1-alpha) (T1A) PDPN GP36 162 PSEC0003 PSEC0025 P07202 PERT_HUMAN Thyroid peroxidase (TPO) (EC 1.11.1.8) TPO 933 Q9BZA8 PC11Y_HUMAN Protocadherin-11 Y-linked (Protocadherin-11) (Protocadherin on the Y chromosome) PCDH11Y PCDH11 1340 (PCDH-Y) (Protocadherin prostate cancer) (Protocadherin-PC) (Protocadherin-22) PCDH22 PCDHY O14917 PCD17_HUMAN Protocadherin-17 (Protocadherin-68) PCDH17 PCDH68 1159 PCH68 Q8TAB3 PCD19_HUMAN Protocadherin-19 PCDH19 KIAA1313 1148 Q9UN73 PCDA6_HUMAN Protocadherin alpha-6 (PCDH-alpha-6) PCDHA6 CNRS2 950 Q9Y5I2 PCDAA_HUMAN Protocadherin alpha-10 (PCDH-alpha-10) PCDHA10 CNRS8 948 Q9UN75 PCDAC_HUMAN Protocadherin alpha-12 (PCDH-alpha-12) PCDHA12 941 Q9Y5F3 PCDB1_HUMAN Protocadherin beta-1 (PCDH-beta-1) PCDHB1 818 Q9Y5E4 PCDB5_HUMAN Protocadherin beta-5 (PCDH-beta-5) PCDHB5 795 Q9UN66 PCDB8_HUMAN Protocadherin beta-8 (PCDH-beta-8) (Protocadherin-3I) PCDHB8 PCDH3I 801 Q9Y5F2 PCDBB_HUMAN Protocadherin beta-11 (PCDH-beta-11) PCDHB11 797 Q9Y5F0 PCDBD_HUMAN Protocadherin beta-13 (PCDH-beta-13) PCDHB13 798 UNQ332/PRO531 Q9Y5H1 PCDG2_HUMAN Protocadherin gamma-A2 (PCDH-gamma-A2) PCDHGA2 932 Q9Y5G4 PCDG9_HUMAN Protocadherin gamma-A9 (PCDH-gamma-A9) PCDHGA9 932 O60330 PCDGC_HUMAN Protocadherin gamma-A12 (PCDH-gamma-A12) (Cadherin-21) (Fibroblast cadherin-3) PCDHGA12 CDH21 932 FIB3 KIAA0588 UNQ371/PRO707 Q9Y5G2 PCDGE_HUMAN Protocadherin gamma-B2 (PCDH-gamma-B2) PCDHGB2 931 Q9Y5F9 PCDGI_HUMAN Protocadherin gamma-B6 (PCDH-gamma-B6) PCDHGB6 930 Q9UN70 PCDGK_HUMAN Protocadherin gamma-C3 (PCDH-gamma-C3) (Protocadherin-2) (Protocadherin-43) (PC- PCDHGC3 PCDH2 934 43) O60245 PCDH7_HUMAN Protocadherin-7 (Brain-heart protocadherin) (BH-Pcdh) PCDH7 BHPCDH 1069 Q16549 PCSK7_HUMAN Proprotein convertase subtilisin/kexin type 7 (EC 3.4.21.—) (Lymphoma proprotein PCSK7 LPC PC7 785 convertase) (Prohormone convertase 7) (Proprotein convertase 7) (PC7) (Proprotein PC8 SPC7 convertase 8) (PC8) (hPC8) (Subtilisin/kexin-like protease PC7) Q9BQ51 PD1L2_HUMAN Programmed cell death 1 ligand 2 (PD-1 ligand 2) (PD-L2) (PDCD1 ligand 2) PDCD1LG2 B7DC 273 (Programmed death ligand 2) (Butyrophilin B7-DC) (B7-DC) (CD antigen CD273) CD273 PDCD1L2 PDL2 P16284 PECA1_HUMAN Platelet endothelial cell adhesion molecule (PECAM-1) (EndoCAM) (GPIIA′) (PECA1) PECAM1 738 (CD antigen CD31) Q9NPG4 PCD12_HUMAN Protocadherin-12 (Vascular cadherin-2) (Vascular endothelial cadherin-2) (VE-cad-2) PCDH12 1184 (VE-cadherin-2) UNQ395/PRO731 Q9Y5H9 PCDA2_HUMAN Protocadherin alpha-2 (PCDH-alpha-2) PCDHA2 948 Q9UN72 PCDA7_HUMAN Protocadherin alpha-7 (PCDH-alpha-7) PCDHA7 CNRS4 937 Q9Y5H6 PCDA8_HUMAN Protocadherin alpha-8 (PCDH-alpha-8) PCDHA8 950 Q9Y5H5 PCDA9_HUMAN Protocadherin alpha-9 (PCDH-alpha-9) PCDHA9 KIAA0345 950 Q9Y5E2 PCDB7_HUMAN Protocadherin beta-7 (PCDH-beta-7) PCDHB7 793 Q9Y5E1 PCDB9_HUMAN Protocadherin beta-9 (PCDH-beta-9) (Protocadherin-3H) PCDHB9 PCDH3H 797 Q9Y5E9 PCDBE_HUMAN Protocadherin beta-14 (PCDH-beta-14) PCDHB14 798 Q9NRJ7 PCDBG_HUMAN Protocadherin beta-16 (PCDH-beta-16) (Protocadherin-3X) PCDHB16 776 KIAA1621 PCDH3X Q9H158 PCDC1_HUMAN Protocadherin alpha-C1 (PCDH-alpha-C1) PCDHAC1 963 Q9Y5H4 PCDG1_HUMAN Protocadherin gamma-A1 (PCDH-gamma-A1) PCDHGA1 931 Q9Y5G9 PCDG4_HUMAN Protocadherin gamma-A4 (PCDH-gamma-A4) PCDHGA4 931 Q9Y5G3 PCDGD_HUMAN Protocadherin gamma-B1 (PCDH-gamma-B1) PCDHGB1 927 Q9UN71 PCDGG_HUMAN Protocadherin gamma-B4 (PCDH-gamma-B4) (Cadherin-20) (Fibroblast cadherin-2) PCDHGB4 CDH20 923 FIB2 Q9Y5G0 PCDGH_HUMAN Protocadherin gamma-B5 (PCDH-gamma-B5) PCDHGB5 923 Q9Y5F8 PCDGJ_HUMAN Protocadherin gamma-B7 (PCDH-gamma-B7) PCDHGB7 929 Q9Y5F7 PCDGL_HUMAN Protocadherin gamma-C4 (PCDH-gamma-C4) PCDHGC4 938 P09619 PGFRB_HUMAN Platelet-derived growth factor receptor beta (PDGF-R-beta) (PDGFR-beta) (EC 2.7.10.1) PDGFRB PDGFR 1106 (Beta platelet-derived growth factor receptor) (Beta-type platelet-derived growth factor PDGFR1 receptor) (CD140 antigen-like family member B) (Platelet-derived growth factor receptor 1) (PDGFR-1) (CD antigen CD140b) Q15116 PDCD1_HUMAN Programmed cell death protein 1 (Protein PD-1) (hPD-1) (CD antigen CD279) PDCD1 PD1 288 P16234 PGFRA_HUMAN Platelet-derived growth factor receptor alpha (PDGF-R-alpha) (PDGFR-alpha) (EC PDGFRA PDGFR2 1089 2.7.10.1) (Alpha platelet-derived growth factor receptor) (Alpha-type platelet-derived RHEPDGFRA growth factor receptor) (CD140 antigen-like family member A) (CD140a antigen) (Platelet-derived growth factor alpha receptor) (Platelet-derived growth factor receptor 2) (PDGFR-2) (CD antigen CD140a) Q9NZ53 PDXL2_HUMAN Podocalyxin-like protein 2 (Endoglycan) PODXL2 605 UNQ1861/PRO3742 Q6UXB8 PI16_HUMAN Peptidase inhibitor 16 (PI-16) (Cysteine-rich secretory protein 9) (CRISP-9) (PSP94- PI16 CRISP9 463 binding protein) PSPBP PSEC0164 UNQ289/PRO328 Q9UKJ0 PILRB_HUMAN Paired immunoglobulin-like type 2 receptor beta (Activating receptor PILR-beta) (Cell PILRB FDFACT 227 surface receptor FDFACT) PP1551 Q8IYJ0 PIANP_HUMAN PILR alpha-associated neural protein (PILR-associating neural protein) (Paired PIANP C12orf53 282 immunoglobin-like type 2 receptor-associating neural protein) PANP UNQ828/PRO1755 P01833 PIGR_HUMAN Polymeric immunoglobulin receptor (PIgR) (Poly-Ig receptor) (Hepatocellular carcinoma- PIGR 764 associated protein TB6) [Cleaved into: Secretory component] Q9UKJ1 PILRA_HUMAN Paired immunoglobulin-like type 2 receptor alpha (Cell surface receptor FDF03) PILRA 303 (Inhibitory receptor PILR-alpha) Q13018 PLA2R_HUMAN Secretory phospholipase A2 receptor (PLA2-R) (PLA2R) (180 kDa secretory PLA2R1 CLEC13C 1463 phospholipase A2 receptor) (C-type lectin domain family 13 member C) (M-type receptor) [Cleaved into: Soluble secretory phospholipase A2 receptor (Soluble PLA2-R) (Soluble PLA2R)] Q8IUK5 PLDX1_HUMAN Plexin domain-containing protein 1 (Tumor endothelial marker 3) (Tumor endothelial PLXDC1 TEM3 500 marker 7) TEM7 O43157 PLXB1_HUMAN Plexin-B1 (Semaphorin receptor SEP) PLXNB1 KIAA0407 2135 PLXN5 SEP O60486 PLXC1_HUMAN Plexin-C1 (Virus-encoded semaphorin protein receptor) (CD antigen CD232) PLXNC1 VESPR 1568 Q969N2 PIGT_HUMAN GPI transamidase component PIG-T (Phosphatidylinositol-glycan biosynthesis class T PIGT CGI-06 578 protein) PSEC0163 UNQ716/PRO1379 P08F94 PKHD1_HUMAN Fibrocystin (Polycystic kidney and hepatic disease 1 protein) (Polyductin) (Tigmin) PKHD1 FCYT 4074 TIGM1 Q6P1J6 PLB1_HUMAN Phospholipase B1, membrane-associated (Phospholipase B) (hPLB) (Phospholipase PLB1 PLB 1458 B/lipase) (PLB/LIP) [Includes: Phospholipase A2 (EC 3.1.1.4); Lysophospholipase (EC 3.1.1.5)] Q8TEM1 PO210_HUMAN Nuclear pore membrane glycoprotein 210 (Nuclear pore protein gp210) (Nuclear NUP210 KIAA0906 1887 envelope pore membrane protein POM 210) (POM210) (Nucleoporin Nup210) (Pore PSEC0245 membrane protein of 210 kDa) O00168 PLM_HUMAN Phospholemman (FXYD domain-containing ion transport regulator 1) FXYD1 PLM 92 P51805 PLXA3_HUMAN Plexin-A3 (Plexin-4) (Semaphorin receptor SEX) PLXNA3 PLXN4 1871 SEX Q9UIW2 PLXA1_HUMAN Plexin-A1 (Semaphorin receptor NOV) PLXNA1 NOV 1896 PLXN1 O75051 PLXA2_HUMAN Plexin-A2 (Semaphorin receptor OCT) PLXNA2 KIAA0463 1894 OCT PLXN2 UNQ209/PRO235 Q8TBF5 PIGX_HUMAN Phosphatidylinositol-glycan biosynthesis class X protein (PIG-X) PIGX 258 P40967 PMEL_HUMAN Melanocyte protein PMEL (ME20-M) (ME20M) (Melanocyte protein Pmel 17) PMEL D12S53E 661 (Melanocytes lineage-specific antigen GP100) (Melanoma-associated ME20 antigen) PMEL17 SILV (P1) (P100) (Premelanosome protein) (Silver locus protein homolog) [Cleaved into: M- alpha (95 kDa melanocyte-specific secreted glycoprotein) (P26) (Secreted melanoma- associated ME20 antigen) (ME20-S) (ME20S); M-beta] Q8IY17 PLPL6_HUMAN Neuropathy target esterase (EC 3.1.1.5) (Patatin-like phospholipase domain-containing PNPLA6 NTE 1366 protein 6) Q9BZG2 PPAT_HUMAN Testicular acid phosphatase (EC 3.1.3.2) ACPT 426 Q86XR5 PRIMA_HUMAN Praline-rich membrane anchor 1 (PRiMA) PRIMA1 153 Q9HCM2 PLXA4_HUMAN Plexin-A4 PLXNA4 KIAA1550 1894 PLXNA4A PLXNA4B UNQ2820/PRO34003 O15031 PLXB2_HUMAN Plexin-B2 (MM1) PLXNB2 KIAA0315 1838 Q9ULL4 PLXB3_HUMAN Plexin-B3 PLXNB3 KIAA1206 1909 PLXN6 O00592 PODXL_HUMAN Podocalyxin (GCTM-2 antigen) (Gp200) (Podocalyxin-like protein 1) (PC) (PCLP-1) PODXL PCLP 558 PCLP1 Q8N131 PORIM_HUMAN Porimin (Keratinocytes-associated transmembrane protein 3) (KCT-3) (Pro-oncosis TMEM123 KCT3 208 receptor inducing membrane injury) (Transmembrane protein 123) PSEC0111 UNQ641/PRO1271 P15309 PPAP_HUMAN Prostatic acid phosphatase (PAP) (EC 3.1.3.2) (5′-nucleotidase) (5′-NT) (EC 3.1.3.5) ACPP 386 (Ecto-5′-nucleotidase) (Thiamine monophosphatase) (TMPase) [Cleaved into: PAPf39] Q5SGD2 PPM1L_HUMAN Protein phosphatase 1L (EC 3.1.3.16) (Protein phosphatase 1-like) (Protein phosphatase PPM1L PP2CE 360 2C isoform epsilon) (PP2C-epsilon) P16471 PRLR_HUMAN Prolactin receptor (PRL-R) PRLR 622 Q6UWB4 PRS55_HUMAN Serine protease 55 (EC 3.4.21.—) (Testis serine protease 1) (T-SP1) PRSS55 TSP1 352 UNQ9391/PRO34284 P10586 PTPRF_HUMAN Receptor-type tyrosine-protein phosphatase F (EC 3.1.3.48) (Leukocyte common antigen PTPRF LAR 1907 related) (LAR) P28827 PTPRM_HUMAN Receptor-type tyrosine-protein phosphatase mu (Protein-tyrosine phosphatase mu) (R- PTPRM PTPRL1 1452 PTP-mu) (EC 3.1.3.48) Q16849 PTPRN_HUMAN Receptor-type tyrosine-protein phosphatase-like N (R-PTP-N) (Islet cell antigen 512) (ICA PTPRN ICA3 979 512) (Islet cell autoantigen 3) (PTP IA-2) ICA512 Q13332 PTPRS_HUMAN Receptor-type tyrosine-protein phosphatase S (R-PTP-S) (EC 3.1.3.48) (Receptor-type PTPRS 1948 tyrosine-protein phosphatase sigma) (R-PTP-sigma) Q6ISU1 PTCRA_HUMAN Pre T-cell antigen receptor alpha (pT-alpha) (pTa) (pT-alpha-TCR) PTCRA 281 P53801 PTTG_HUMAN Pituitary tumor-transforming gene 1 protein-interacting protein (Pituitary tumor- PTTG1IP C21orf1 180 transforming gene protein-binding factor) (PBF) (PTTG-binding factor) C21orf3 Q13308 PTK7_HUMAN Inactive tyrosine-protein kinase 7 (Colon carcinoma kinase 4) (CCK-4) (Protein-tyrosine PTK7 CCK4 1070 kinase 7) (Pseudo tyrosine kinase receptor 7) (Tyrosine-protein kinase-like 7) P23468 PTPRD_HUMAN Receptor-type tyrosine-protein phosphatase delta (Protein-tyrosine phosphatase delta) PTPRD 1912 (R-PTP-delta) (EC 3.1.3.48) Q15262 PTPRK_HUMAN Receptor-type tyrosine-protein phosphatase kappa (Protein-tyrosine phosphatase kappa) PTPRK PTPK 1439 (R-PTP-kappa) (EC 3.1.3.48) Q9UMZ3 PTPRQ_HUMAN Phosphatidylinositol phosphatase PTPRQ (EC 3.1.3.—) (Receptor-type tyrosine-protein PTPRQ 2332 phosphatase Q) (PTP-RQ) (R-PTP-Q) (EC 3.1.3.48) P23467 PTPRB_HUMAN Receptor-type tyrosine-protein phosphatase beta (Protein-tyrosine phosphatase beta) (R- PTPRB PTPB 1997 PTP-beta) (EC 3.1.3.48) (Vascular endothelial protein tyrosine phosphatase) (VE-PTP) Q9HD43 PTPRH_HUMAN Receptor-type tyrosine-protein phosphatase H (R-PTP-H) (EC 3.1.3.48) (Stomach PTPRH SAP1 1115 cancer-associated protein tyrosine phosphatase 1) (SAP-1) (Transmembrane-type protein-tyrosine phosphatase type H) Q16827 PTPRO_HUMAN Receptor-type tyrosine-protein phosphatase O (R-PTP-O) (EC 3.1.3.48) (Glomerular PTPRO GLEPP1 1216 epithelial protein 1) (Protein tyrosine phosphatase U2) (PTP-U2) (PTPase U2) PTPU2 Q15256 PTPRR_HUMAN Receptor-type tyrosine-protein phosphatase R (R-PTP-R) (EC 3.1.3.48) (Ch-1PTPase) PTPRR ECPTP 657 (NC-PTPCOM1) (Protein-tyrosine phosphatase PCPTP1) PTPRQ P15151 PVR_HUMAN Poliovirus receptor (Nectin-like protein 5) (NECL-5) (CD antigen CD155) PVR PVS 417 P18433 PTPRA_HUMAN Receptor-type tyrosine-protein phosphatase alpha (Protein-tyrosine phosphatase alpha) PTPRA PTPA 802 (R-PTP-alpha) (EC 3.1.3.48) PTPRL2 P08575 PTPRC_HUMAN Receptor-type tyrosine-protein phosphatase C (EC 3.1.3.48) (Leukocyte common PTPRC CD45 1304 antigen) (L-CA) (T200) (CD antigen CD45) O14522 PTPRT_HUMAN Receptor-type tyrosine-protein phosphatase T (R-PTP-T) (EC 3.1.3.48) (Receptor-type PTPRT KIAA0283 1441 tyrosine-protein phosphatase rho) (RPTP-rho) Q92729 PTPRU_HUMAN Receptor-type tyrosine-protein phosphatase U (R-PTP-U) (EC 3.1.3.48) (Pancreatic PTPRU FMI PCP2 1446 carcinoma phosphatase 2) (PCP-2) (Protein-tyrosine phosphatase J) (PTP-J) (hPTP-J) PTPRO (Protein-tyrosine phosphatase pi) (PTP pi) (Protein-tyrosine phosphatase receptor omicron) (PTP-RO) (Receptor-type protein-tyrosine phosphatase psi) (R-PTP-psi) P23471 PTPRZ_HUMAN Receptor-type tyrosine-protein phosphatase zeta (R-PTP-zeta) (EC 3.1.3.48) (Protein- PTPRZ1 HTPZP2 2315 tyrosine phosphatase receptor type Z polypeptide 1) (Protein-tyrosine phosphatase PTPRZ PTPRZ2 receptor type Z polypeptide 2) (R-PTP-zeta-2) PTPZ Q9NXS2 QPCTL_HUMAN Glutaminyl-peptide cyclotransferase-like protein (EC 2.3.2.5) (Golgi-resident glutaminyl- QPCTL 382 peptide cyclotransferase) (isoQC) (gQC) Q92932 PTPR2_HUMAN Receptor-type tyrosine-protein phosphatase N2 (R-PTP-N2) (EC 3.1.3.48) (Islet cell PTPRN2 KIAA0387 1015 autoantigen-related protein) (IAR) (ICAAR) (Phogrin) P23469 PTPRE_HUMAN Receptor-type tyrosine-protein phosphatase epsilon (Protein-tyrosine phosphatase PTPRE 700 epsilon) (R-PTP-epsilon) (EC 3.1.3.48) P23470 PTPRG_HUMAN Receptor-type tyrosine-protein phosphatase gamma (Protein-tyrosine phosphatase PTPRG PTPG 1445 gamma) (R-PTP-gamma) (EC 3.1.3.48) Q12913 PTPRJ_HUMAN Receptor-type tyrosine-protein phosphatase eta (Protein-tyrosine phosphatase eta) (R- PTPRJ DEP1 1337 PTP-eta) (EC 3.1.3.48) (Density-enhanced phosphatase 1) (DEP-1) (HPTP eta) (Protein- tyrosine phosphatase receptor type J) (R-PTP-J) (CD antigen CD148) Q15109 RAGE_HUMAN Advanced glycosylation end product-specific receptor (Receptor for advanced AGER RAGE 404 glycosylation end products) Q6UX71 PXDC2_HUMAN Plexin domain-containing protein 2 (Tumor endothelial marker 7-related protein) PLXDC2 TEM7R 529 UNQ2514/PRO6003 O60894 RAMP1_HUMAN Receptor activity-modifying protein 1 (Calcitonin-receptor-like receptor activity-modifying RAMP1 148 protein 1) (CRLR activity-modifying protein 1) O60895 RAMP2_HUMAN Receptor activity-modifying protein 2 (Calcitonin-receptor-like receptor activity-modifying RAMP2 175 protein 2) (CRLR activity-modifying protein 2) O60896 RAMP3_HUMAN Receptor activity-modifying protein 3 (Calcitonin-receptor-like receptor activity-modifying RAMP3 148 protein 3) (CRLR activity-modifying protein 3) Q8IUW5 RELL1_HUMAN RELT-like protein 1 RELL1 PSEC0162 271 O75787 RENR_HUMAN Renin receptor (ATPase H(+)-transporting lysosomal accessory protein 2) (ATPase H(+)- ATP6AP2 ATP6IP2 350 transporting lysosomal-interacting protein 2) (ER-localized type I transmembrane adaptor) CAPER ELDF10 (Embryonic liver differentiation factor 10) (N14F) (Renin/prorenin receptor) (Vacuolar ATP HT028 MSTP009 synthase membrane sector-associated protein M8-9) (ATP6M8-9) (V-ATPase M8.9 PSEC0072 subunit) Q6H3X3 RET1G_HUMAN Retinoic acid early transcript 1G protein (UL-16 binding protein 5) (ULBP5) RAET1G 334 P07949 RET_HUMAN Proto-oncogene tyrosine-protein kinase receptor Ret (EC 2.7.10.1) (Cadherin family RET CDHF12 1114 member 12) (Proto-oncogene c-Ret) [Cleaved into: Soluble RET kinase fragment; CDHR16 PTC Extracellular cell-membrane anchored RET cadherin 120 kDa fragment] RET51 Q9ULK6 RN150_HUMAN RING finger protein 150 RNF150 KIAA1214 438 Q9Y6N7 ROBO1_HUMAN Roundabout homolog 1 (Deleted in U twenty twenty) (H-Robo-1) ROBO1 DUTT1 1651 Q01974 ROR2_HUMAN Tyrosine-protein kinase transmembrane receptor ROR2 (EC 2.7.10.1) (Neurotrophic ROR2 NTRKR2 943 tyrosine kinase, receptor-related 2) P04843 RPN1_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) RPN1 607 (Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 67 kDa subunit) (Ribophorin I) (RPN-I) (Ribophorin-1) Q68DV7 RNF43_HUMAN E3 ubiquitin-protein ligase RNF43 (EC 6.3.2.—) (RING finger protein 43) RNF43 783 Q04912 RON_HUMAN Macrophage-stimulating protein receptor (MSP receptor) (EC 2.7.10.1) (CDw136) MST1R PTK8 RON 1400 (Protein-tyrosine kinase 8) (p185-Ron) (CD antigen CD136) [Cleaved into: Macrophage- stimulating protein receptor alpha chain; Macrophage-stimulating protein receptor beta chain] Q96MS0 ROBO3_HUMAN Roundabout homolog 3 (Roundabout-like protein 3) ROBO3 1386 Q01973 ROR1_HUMAN Inactive tyrosine-protein kinase transmembrane receptor ROR1 (Neurotrophic tyrosine ROR1 NTRKR1 937 kinase, receptor-related 1) P08922 ROS1_HUMAN Proto-oncogene tyrosine-protein kinase ROS (EC 2.7.10.1) (Proto-oncogene c-Ros) ROS1 MCF3 ROS 2347 (Proto-oncogene c-Ros-1) (Receptor tyrosine kinase c-ros oncogene 1) (c-Ros receptor tyrosine kinase) Q9HCK4 ROBO2_HUMAN Roundabout homolog 2 ROBO2 KIAA1568 1378 P34925 RYK_HUMAN Tyrosine-protein kinase RYK (EC 2.7.10.1) RYK JTK5A 604 Q9HBV2 SACA1_HUMAN Sperm acrosome membrane-associated protein 1 (Sperm acrosomal membrane- SPACA1 SAMP32 294 associated protein 32) P31431 SDC4_HUMAN Syndecan-4 (SYND4) (Amphiglycan) (Ryudocan core protein) SDC4 198 P21583 SCF_HUMAN Kit ligand (Mast cell growth factor) (MGF) (Stem cell factor) (SCF) (c-Kit ligand) [Cleaved KITLG MGF SCF 273 into: Soluble KIT ligand (sKITLG)] O60939 SCN2B_HUMAN Sodium channel subunit beta-2 SCN2B 215 UNQ326/PRO386 Q8IWT1 SCN4B_HUMAN Sodium channel subunit beta-4 SCN4B 228 P18827 SDC1_HUMAN Syndecan-1 (SYND1) (CD antigen CD138) SDC1 SDC 310 O75056 SDC3_HUMAN Syndecan-3 (SYND3) SDC3 KIAA0468 442 Q9NTN9 SEM4G_HUMAN Semaphorin-4G SEMA4G KIAA1619 838 W5XKT8 SACA6_HUMAN Sperm acrosome membrane-associated protein 6 (BACHELOR-like protein) SPACA6 SPACA6P 324 UNQ2487/PRO5774 Q96BY9 SARAF_HUMAN Store-operated calcium entry-associated regulatory factor (SARAF) (SOCE-associated SARAF TMEM66 339 regulatory factor) (HBV X-transactivated gene 3 protein) (HBV XAg-transactivated protein XTP3 HSPC035 3) (Protein FOAP-7) (Transmembrane protein 66) NPD003 PSEC0019 UNQ1967/PRO4499 Q13591 SEM5A_HUMAN Semaphorin-5A (Semaphorin-F) (Sema F) SEMA5A SEMAF 1074 Q53EL9 SEZ6_HUMAN Seizure protein 6 homolog (SEZ-6) (hSEZ-6) SEZ6 994 Q9NY72 SCN3B_HUMAN Sodium channel subunit beta-3 SCN3B KIAA1158 215 Q8WVN6 SCTM1_HUMAN Secreted and transmembrane protein 1 (Protein K-12) SECTM1 K12 248 Q9UBV2 SE1L1_HUMAN Protein sel-1 homolog 1 (Suppressor of lin-12-like protein 1) (Sel-1L) SEL1L TSA305 794 UNQ128/PRO1063 Q9NPR2 SEM4B_HUMAN Semaphorin-4B SEMA4B KIAA1745 832 SEMAC UNQ749/PRO1480 O95754 SEM4F_HUMAN Semaphorin-4F (Semaphorin-M) (Sema M) (Semaphorin-W) (Sema W) SEMA4F SEMAM 770 SEMAW Q96RL6 SIG11_HUMAN Sialic acid-binding Ig-like lectin 11 (Sialic acid-binding lectin 11) (Siglec-11) SIGLEC11 698 UNQ9222/PRO28718 Q07699 SCN1B_HUMAN Sodium channel subunit beta-1 SCN1B 218 P34741 SDC2_HUMAN Syndecan-2 (SYND2) (Fibroglycan) (Heparan sulfate proteoglycan core protein) (HSPG) SDC2 HSPG1 201 (CD antigen CD362) Q7Z5N4 SDK1_HUMAN Protein sidekick-1 SDK1 2213 Q58EX2 SDK2_HUMAN Protein sidekick-2 SDK2 KIAA1514 2172 Q5TEA6 SE1L2_HUMAN Protein sel-1 homolog 2 (Suppressor of lin-12-like protein 2) (Sel-1L2) SEL1L2 C20orf50 688 Q9BYH1 SE6L1_HUMAN Seizure 6-like protein SEZ6L KIAA0927 1024 UNQ2542/PRO6094 Q14242 SELPL_HUMAN P-selectin glycoprotein ligand 1 (PSGL-1) (Selectin P ligand) (CD antigen CD162) SELPLG 412 Q9H3T2 SEM6C_HUMAN Semaphorin-6C (Semaphorin-Y) (Sema Y) SEMA6C KIAA1869 930 SEMAY Q96DD7 SHSA4_HUMAN Protein shisa-4 (Transmembrane protein 58) SHISA4 C1orf40 197 TMEM58 UNQ583/PRO1153 Q9P0V8 SLAF8_HUMAN SLAM family member 8 (B-lymphocyte activator macrophage expressed) (BCM-like SLAMF8 BLAME 285 membrane protein) (CD antigen CD353) Q9H3T3 SEM6B_HUMAN Semaphorin-6B (Semaphorin-Z) (Sema Z) SEMA6B SEMAN 888 SEMAZ UNQ1907/PRO4353 Q8NFY4 SEM6D_HUMAN Semaphorin-6D SEMA6D KIAA1479 1073 O94933 SLIK3_HUMAN SLIT and NTRK-like protein 3 SLITRK3 KIAA0848 977 Q6UXD5 SE6L2_HUMAN Seizure 6-like protein 2 SEZ6L2 PSK 910 UNQ1903/PRO4349 Q9C0C4 SEM4C_HUMAN Semaphorin-4C SEMA4C KIAA1739 833 SEMAI UNQ5855/PRO34487 Q92854 SEM4D_HUMAN Semaphorin-4D (A8) (BB18) (GR3) (CD antigen CD100) SEMA4D C9orf164 862 CD100 SEMAJ P78324 SHPS1_HUMAN Tyrosine-protein phosphatase non-receptor type substrate 1 (SHP substrate 1) (SHPS-1) SIRPA BIT MFR 504 (Brain Ig-like molecule with tyrosine-based activation motifs) (Bit) (CD172 antigen-like MYD1 PTPNS1 family member A) (Inhibitory receptor SHPS-1) (Macrophage fusion receptor) (MyD-1 SHPS1 SIRP antigen) (Signal-regulatory protein alpha-1) (Sirp-alpha-1) (Signal-regulatory protein alpha-2) (Sirp-alpha-2) (Signal-regulatory protein alpha-3) (Sirp-alpha-3) (p84) (CD antigen CD172a) Q8N114 SHSA5_HUMAN Protein shisa-5 (Putative NF-kappa-B-activating protein 120) (Scotin) SHISA5 SCOTIN 240 PSEC0133 B8ZZ34 SHSA8_HUMAN Putative protein shisa-8 SHISA8 C22orf17 492 Q96PQ1 SIG12_HUMAN Sialic acid-binding Ig-like lectin 12 (Siglec-12) (Sialic acid-binding Ig-like lectin-like 1) SIGLEC12 595 (Siglec-L1) SIGLECL1 SLG UNQ9215/PRO34042 Q5JXA9 SIRB2_HUMAN Signal-regulatory protein beta-2 (SIRP-beta-2) (Protein tyrosine phosphatase non- SIRPB2 PTPN1L 342 receptor type substrate 1-like 3) (Protein tyrosine phosphatase non-receptor type PTPNS1L3 substrate protein) Q9P1W8 SIRPG_HUMAN Signal-regulatory protein gamma (SIRP-gamma) (CD172 antigen-like family member B) SIRPG SIRPB2 387 (Signal-regulatory protein beta-2) (SIRP-b2) (SIRP-beta-2) (CD antigen CD172g) Q9BQ49 SMIM7_HUMAN Small integral membrane protein 7 SMIM7 C19orf42 75 Q9H3S1 SEM4A_HUMAN Semaphorin-4A (Semaphorin-B) (Sema B) SEMA4A SEMAB 761 SEMB UNQ783/PRO1317 Q9H2E6 SEM6A_HUMAN Semaphorin-6A (Semaphorin VIA) (Sema VIA) (Semaphorin-6A-1) (SEMA6A-1) SEMA6A KIAA1368 1030 SEMAQ B4DS77 SHSA9_HUMAN Protein shisa-9 SHISA9 424 A6NMB1 SIG16_HUMAN Sialic acid-binding Ig-like lectin 16 (Siglec-16) (Siglec-P16) SIGLEC16 481 SIGLECP16 Q9NYZ4 SIGL8_HUMAN Sialic acid-binding Ig-like lectin 8 (Siglec-8) (Sialoadhesin family member 2) (SAF-2) SIGLEC8 SAF2 499 Q9UIB8 SLAF5_HUMAN SLAM family member 5 (Cell surface antigen MAX.3) (Hly9-beta) (Leukocyte CD84 SLAMF5 345 differentiation antigen CD84) (Signaling lymphocytic activation molecule 5) (CD antigen CD84) Q16586 SGCA_HUMAN Alpha-sarcoglycan (Alpha-SG) (50 kDa dystrophin-associated glycoprotein) (50DAG) SGCA ADL DAG2 387 (Adhalin) (Dystroglycan-2) A0PJX4 SHSA3_HUMAN Protein shisa-3 homolog SHISA3 238 Q96LC7 SIG10_HUMAN Sialic acid-binding Ig-like lectin 10 (Siglec-10) (Siglec-like protein 2) SIGLEC10 SLG2 697 UNQ477/PRO940 O15389 SIGL5_HUMAN Sialic acid-binding Ig-like lectin 5 (Siglec-5) (CD33 antigen-like 2) (Obesity-binding protein SIGLEC5 CD33L2 551 2) (OB-BP2) (OB-binding protein 2) (CD antigen CD170) OBBP2 O43699 SIGL6_HUMAN Sialic acid-binding Ig-like lectin 6 (Siglec-6) (CD33 antigen-like 1) (CDw327) (Obesity- SIGLEC6 CD33L 453 binding protein 1) (OB-BP1) (CD antigen CD327) CD33L1 OBBP1 Q9Y336 SIGL9_HUMAN Sialic acid-binding Ig-like lectin 9 (Siglec-9) (CDw329) (Protein FOAP-9) (CD antigen SIGLEC9 463 CD329) UNQ668/PRO1302 O00241 SIRB1_HUMAN Signal-regulatory protein beta-1 (SIRP-beta-1) (CD172 antigen-like family member B) SIRPB1 398 (CD antigen CD172b) Q13291 SLAF1_HUMAN Signaling lymphocytic activation molecule (CDw150) (IPO-3) (SLAM family member 1) SLAMF1 SLAM 335 (CD antigen CD150) Q96DU3 SLAF6_HUMAN SLAM family member 6 (Activating NK receptor) (NK-T-B-antigen) (NTB-A) (CD antigen SLAMF6 KALI 332 CD352) UNQ6123/PRO20080 O94991 SLIK5_HUMAN SLIT and NTRK-like protein 5 (Leucine-rich repeat-containing protein 11) SLITRK5 KIAA0918 958 LRRC11 Q96PQ0 SORC2_HUMAN VPS10 domain-containing receptor SorCS2 SORCS2 KIAA1329 1159 Q6UWI4 SHSA2_HUMAN Protein shisa-2 homolog (Transmembrane protein 46) SHISA2 C13orf13 295 TMEM46 UNQ9166/PRO28631 Q6ZMC9 SIG15_HUMAN Sialic acid-binding Ig-like lectin 15 (Siglec-15) (CD33 antigen-like 3) SIGLEC15 CD33L3 328 Q9Y286 SIGL7_HUMAN Sialic acid-binding Ig-like lectin 7 (Siglec-7) (Adhesion inhibitory receptor molecule 1) SIGLEC7 AIRM1 467 (AIRM-1) (CDw328) (D-siglec) (QA79 membrane protein) (p75) (CD antigen CD328) Q96A28 SLAF9_HUMAN SLAM family member 9 (CD2 family member 10) (CD2F-10) (CD84 homolog 1) (CD84- SLAMF9 CD2F10 289 H1) UNQ1938/PRO4421 Q9H156 SLIK2_HUMAN SLIT and NTRK-like protein 2 SLITRK2 CXorf2 845 KIAA1854 SLITL1 UNQ9197/PRO34756 Q8IW52 SLIK4_HUMAN SLIT and NTRK-like protein 4 SLITRK4 837 A6NGZ8 SMIM9_HUMAN Small integral membrane protein 9 SMIM9 CXorf68 99 Q8WY21 SORC1_HUMAN VPS10 domain-containing receptor SorCS1 (hSorCS) SORCS1 SORCS 1168 Q92673 SORL_HUMAN Sortilin-related receptor (Low-density lipoprotein receptor relative with 11 ligand-binding SORL1 C11orf32 2214 repeats) (LDLR relative with 11 ligand-binding repeats) (LR11) (SorLA-1) (Sorting protein- related receptor containing LDLR class A repeats) (SorLA) Q99523 SORT_HUMAN Sortilin (100 kDa NT receptor) (Glycoprotein 95) (Gp95) (Neurotensin receptor 3) (NT3) SORT1 831 (NTR3) Q9Y3P8 SIT1_HUMAN Signaling threshold-regulating transmembrane adapter 1 (SHP2-interacting SIT1 SIT 196 transmembrane adapter protein) (Suppression-inducing transmembrane adapter 1) (gp30/40) Q9NQ25 SLAF7_HUMAN SLAM family member 7 (CD2 subset 1) (CD2-like receptor-activating cytotoxic cells) SLAMF7 CS1 335 (CRACC) (Membrane protein FOAP-12) (Novel Ly9) (Protein 19A) (CD antigen CD319) UNQ576/PRO1138 Q96PX8 SLIK1_HUMAN SLIT and NTRK-like protein 1 (Leucine-rich repeat-containing protein 12) SLITRK1 KIAA1910 696 LRRC12 UNQ233/PRO266 Q9H5Y7 SLIK6_HUMAN SLIT and NTRK-like protein 6 SLITRK6 841 Q6ZSJ9 SHSA6_HUMAN Protein shisa-6 homolog SHISA6 500 Q08ET2 SIG14_HUMAN Sialic acid-binding Ig-like lectin 14 (Siglec-14) SIGLEC14 396 UNQ294/PRO333 Q5TFQ8 SIRBL_HUMAN Signal-regulatory protein beta-1 isoform 3 (SIRP-beta-1 isoform 3) SIRPB1 398 Q9UPU3 SORC3_HUMAN VPS10 domain-containing receptor SorCS3 SORCS3 KIAA1059 1222 O43291 SPIT2_HUMAN Kunitz-type protease inhibitor 2 (Hepatocyte growth factor activator inhibitor type 2) (HAI- SPINT2 HAI2 KOP 252 2) (Placental bikunin) Q9BZZ2 SN_HUMAN Sialoadhesin (Sialic acid-binding Ig-like lectin 1) (Siglec-1) (CD antigen CD169) SIGLEC1 SN 1709 Q9P246 STIM2_HUMAN Stromal interaction molecule 2 STIM2 KIAA1482 746 Q9UBS9 SUCO_HUMAN SUN domain-containing ossification factor (Membrane protein CH1) (Protein SUCO C1orf9 CH1 1254 osteopotentia homolog) (SUN-like protein 1) OPT SLP1 Q96GP6 SREC2_HUMAN Scavenger receptor class F member 2 (SRECRP-1) (Scavenger receptor expressed by SCARF2 SREC2 870 endothelial cells 2 protein) (SREC-II) SREPCR P43307 SSRA_HUMAN Translocon-associated protein subunit alpha (TRAP-alpha) (Signal sequence receptor SSR1 TRAPA 286 subunit alpha) (SSR-alpha) PSEC0262 Q5VX71 SUSD4_HUMAN Sushi domain-containing protein 4 SUSD4 490 UNQ196/PRO222 P43308 SSRB_HUMAN Translocon-associated protein subunit beta (TRAP-beta) (Signal sequence receptor SSR2 TRAPB 183 subunit beta) (SSR-beta) HSD25 P51571 SSRD_HUMAN Translocon-associated protein subunit delta (TRAP-delta) (Signal sequence receptor SSR4 TRAPD 173 subunit delta) (SSR-delta) Q13586 STIM1_HUMAN Stromal interaction molecule 1 STIM1 GOK 685 Q14162 SREC_HUMAN Scavenger receptor class F member 1 (Acetyl LDL receptor) (Scavenger receptor SCARF1 KIAA0149 830 expressed by endothelial cells 1) (SREC-I) SREC Q92537 SUSD6_HUMAN Sushi domain-containing protein 6 (Drug-activated gene overexpressed protein) SUSD6 DRAGO 303 KIAA0247 Q9NY15 STAB1_HUMAN Stabilin-1 (Fasciclin, EGF-like, laminin-type EGF-like and link domain-containing STAB1 FEEL1 2570 scavenger receptor 1) (FEEL-1) (MS-1 antigen) KIAA0246 Q8WWQ8 STAB2_HUMAN Stabilin-2 (FAS1 EGF-like and X-link domain-containing adhesion molecule 2) (Fasciclin, STAB2 FEEL2 2551 EGF-like, laminin-type EGF-like and link domain-containing scavenger receptor 2) (FEEL- FELL FEX2 HARE 2) (Hyaluronan receptor for endocytosis) [Cleaved into: 190 kDa form stabilin-2 (190 kDa hyaluronan receptor for endocytosis)] O60279 SUSD5_HUMAN Sushi domain-containing protein 5 SUSD5 KIAA0527 629 Q9UGT4 SUSD2_HUMAN Sushi domain-containing protein 2 SUSD2 822 Q9UQF0 SYCY1_HUMAN Syncytin-1 (Endogenous retrovirus group W member 1) (Env-W) (Envelope polyprotein ERVW-1 ERVWE1 538 gPr73) (Enverin) (HERV-7q Envelope protein) (HERV-W envelope protein) (HERV- W_7q21.2 provirus ancestral Env polyprotein) (Syncytin) [Cleaved into: Surface protein (SU) (gp50); Transmembrane protein (TM) (gp24)] Q6UWL2 SUSD1_HUMAN Sushi domain-containing protein 1 SUSD1 747 UNQ2438/PRO4999 Q8N3T6 T132C_HUMAN Transmembrane protein 132C TMEM132C 1108 A2VDJ0 T131L_HUMAN Transmembrane protein 131-like KIAA0922 1609 TMEM131L Q6IEE7 T132E_HUMAN Transmembrane protein 132E TMEM132E 984 Q14DG7 T132B_HUMAN Transmembrane protein 132B TMEM132B 1078 KIAA1786 KIAA1906 P09758 TACD2_HUMAN Tumor-associated calcium signal transducer 2 (Cell surface glycoprotein Trop-2) TACSTD2 GA733-1 323 (Membrane component chromosome 1 surface marker 1) (Pancreatic carcinoma marker M1S1 TROP2 protein GA733-1) Q14C87 T132D_HUMAN Transmembrane protein 132D (Mature oligodendrocytes transmembrane protein) (Mature TMEM132D 1099 OL transmembrane protein) HBE120 KIAA1944 MOLT Q96GX1 TECT2_HUMAN Tectonic-2 TCTN2 C12orf38 697 TECT2 Q24JP5 T132A_HUMAN Transmembrane protein 132A (HSPA5-binding protein 1) TMEM132A 1023 HSPA5BP1 KIAA1583 B6A8C7 TARM1_HUMAN T-cell-interacting, activating receptor on myeloid cells protein 1 (OSCAR-like transcript-2 TARM1 271 protein) (OLT-2) P40200 TACT_HUMAN T-cell surface protein tactile (Cell surface antigen CD96) (T cell-activated increased late CD96 585 expression protein) (CD antigen CD96) Q9UIK5 TEFF2_HUMAN Tomoregulin-2 (TR-2) (Hyperplastic polyposis protein 1) (Transmembrane protein with TMEFF2 HPP1 374 EGF-like and two follistatin-like domains) TENB2 TPEF UNQ178/PRO204 P36897 TGFR1_HUMAN TGF-beta receptor type-1 (TGFR-1) (EC 2.7.11.30) (Activin A receptor type II-like protein TGFBR1 ALK5 503 kinase of 53 kD) (Activin receptor-like kinase 5) (ALK-5) (ALK5) (Serine/threonine-protein SKR4 kinase receptor R4) (SKR4) (TGF-beta type I receptor) (Transforming growth factor-beta receptor type I) (TGF-beta receptor type I) (TbetaR-I) Q9NS62 THSD1_HUMAN Thrombospondin type-1 domain-containing protein 1 (Transmembrane molecule with THSD1 TMTSP 852 thrombospondin module) UNQ3010/PRO9769 Q02763 TIE2_HUMAN Angiopoietin-1 receptor (EC 2.7.10.1) (Endothelial tyrosine kinase) (Tunica interna TEK TIE2 VMCM 1124 endothelial cell kinase) (Tyrosine kinase with Ig and EGF homology domains-2) VMCM1 (Tyrosine-protein kinase receptor TEK) (Tyrosine-protein kinase receptor TIE-2) (hTIE2) (p140 TEK) (CD antigen CD202b) P13726 TF_HUMAN Tissue factor (TF) (Coagulation factor III) (Thromboplastin) (CD antigen CD142) F3 295 Q495A1 TIGIT_HUMAN T-cell immunoreceptor with Ig and ITIM domains (V-set and immunoglobulin domain- TIGIT VSIG9 244 containing protein 9) (V-set and transmembrane domain-containing protein 3) VSTM3 Q03167 TGBR3_HUMAN Transforming growth factor beta receptor type 3 (TGF-beta receptor type 3) (TGFR-3) TGFBR3 851 (Betaglycan) (Transforming growth factor beta receptor III) (TGF-beta receptor type III) O43493 TGON2_HUMAN Trans-Golgi network integral membrane protein 2 (TGN38 homolog) (TGN46) (TGN48) TGOLN2 TGN46 480 (Trans-Golgi network protein TGN51) TGN51 Q9BXR5 TLR10_HUMAN Toll-like receptor 10 (CD antigen CD290) TLR10 811 UNQ315/PRO358 Q8IYR6 TEFF1_HUMAN Tomoregulin-1 (TR-1) (H7365) (Transmembrane protein with EGF-like and one follistatin- TMEFF1 C9orf2 380 like domain) Q8N3G9 TM130_HUMAN Transmembrane protein 130 TMEM130 435 UNQ719/PRO1383 Q4KMG9 TM52B_HUMAN Transmembrane protein 52B TMEM52B C12orf59 183 UNQ5927/PRO19821 Q9BZD6 TMG4_HUMAN Transmembrane gamma-carboxyglutamic acid protein 4 (Praline-rich gamma- PRRG4 PRGP4 226 carboxyglutamic acid protein 4) (Proline-rich Gla protein 4) TMG4 Q8NEW7 TMIE_HUMAN Transmembrane inner ear expressed protein TMIE 156 Q9HBJ8 TMM27_HUMAN Collectrin (Transmembrane protein 27) TMEM27 222 UNQ679/PRO1312 Q6UXU6 TMM92_HUMAN Transmembrane protein 92 TMEM92 159 UNQ5801/PRO19608 Q6NUS6 TECT3_HUMAN Tectonic-3 TCTN3 C10orf61 607 TECT3 PSEC0041 UNQ1881/PRO4324 P35590 TIE1_HUMAN Tyrosine-protein kinase receptor Tie-1 (EC 2.7.10.1) TIE1 TIE 1138 Q15363 TMED2_HUMAN Transmembrane emp24 domain-containing protein 2 (Membrane protein p24A) (p24) TMED2 RNP24 201 (p24 family protein beta-1) (p24beta1) Q7Z7H5 TMED4_HUMAN Transmembrane emp24 domain-containing protein 4 (Endoplasmic reticulum stress- TMED4 ERS25 227 response protein 25) (ERS25) (GMP25iso) (Putative NF-kappa-B-activating protein 156) (p24 family protein alpha-3) (p24alpha3) Q9Y3B3 TMED7_HUMAN Transmembrane emp24 domain-containing protein 7 (p24 family protein gamma-3) TMED7 CGI-109 224 (p24gamma3) (p27) Q07011 TNR9_HUMAN Tumor necrosis factor receptor superfamily member 9 (4-1BB ligand receptor) (CDw137) TNFRSF9 CD137 255 (T-cell antigen 4-1BB homolog) (T-cell antigen ILA) (CD antigen CD137) ILA P01135 TGFA_HUMAN Protransforming growth factor alpha [Cleaved into: Transforming growth factor alpha TGFA 160 (TGF-alpha) (EGF-like TGF) (ETGF) (TGF type 1)] P37173 TGFR2_HUMAN TGF-beta receptor type-2 (TGFR-2) (EC 2.7.11.30) (TGF-beta type II receptor) TGFBR2 567 (Transforming growth factor-beta receptor type II) (TGF-beta receptor type II) (TbetaR-II) Q9UPZ6 THS7A_HUMAN Thrombospondin type-1 domain-containing protein 7A THSD7A KIAA0960 1657 Q9C0I4 THS7B_HUMAN Thrombospondin type-1 domain-containing protein 7B THSD7B KIAA1679 1608 Q96H15 TIMD4_HUMAN T-cell immunoglobulin and mucin domain-containing protein 4 (TIMD-4) (T-cell TIMD4 TIM4 378 immunoglobulin mucin receptor 4) (TIM-4) (T-cell membrane protein 4) Q15399 TLR1_HUMAN Toll-like receptor 1 (Toll/interleukin-1 receptor-like protein) (TIL) (CD antigen CD281) TLR1 KIAA0012 786 O15455 TLR3_HUMAN Toll-like receptor 3 (CD antigen CD283) TLR3 904 O60602 TLR5_HUMAN Toll-like receptor 5 (Toll/interleukin-1 receptor-like protein 3) TLR5 TIL3 858 Q4V9L6 TM119_HUMAN Transmembrane protein 119 (Osteoblast induction factor) (OBIF) TMEM119 283 PSEC0199 UNQ731/PRO1415 Q13445 TMED1_HUMAN Transmembrane emp24 domain-containing protein 1 (Interleukin-1 receptor-like 1 ligand) TMED1 IL1RL1L 227 (Putative T1/ST2 receptor-binding protein) (p24 family protein gamma-1) (Tp24) IL1RL1LG (p24gamma1) Q9Y3A6 TMED5_HUMAN Transmembrane emp24 domain-containing protein 5 (p24 family protein gamma-2) TMED5 CGI-100 229 (p24gamma2) (p28) UNQ397/PRO733 P49755 TMEDA_HUMAN Transmembrane emp24 domain-containing protein 10 (21 kDa transmembrane-trafficking TMED10 TMP21 219 protein) (S31III125) (S31I125) (Tmp-21-I) (Transmembrane protein Tmp21) (p23) (p24 family protein delta-1) (p24delta1) (p24delta) Q86V40 TIKI1_HUMAN Metalloprotease TIKI1 (EC 3.4.—.—) (TRAB domain-containing protein 2A) TRABD2A C2orf89 505 TIKI1 Q9Y2C9 TLR6_HUMAN Toll-like receptor 6 (CD antigen CD286) TLR6 796 Q9NR97 TLR8_HUMAN Toll-like receptor 8 (CD antigen CD288) TLR8 1041 UNQ249/PRO286 Q8WZ59 TM190_HUMAN Transmembrane protein 190 TMEM190 MDAC1 177 Q6UWW9 TM207_HUMAN Transmembrane protein 207 TMEM207 146 UNQ846/PRO1784 Q9UK28 TM59L_HUMAN Transmembrane protein 59-like (Brain-specific membrane-anchored protein) TMEM59L BSMAP 342 C19orf4 Q8WW62 TMED6_HUMAN Transmembrane emp24 domain-containing protein 6 (p24 family protein gamma-5) TMED6 240 (p24gamma5) UNQ9146/PRO34237 Q9BVK6 TMED9_HUMAN Transmembrane emp24 domain-containing protein 9 (GMP25) (Glycoprotein 25L2) (p24 TMED9 GP25L2 235 family protein alpha-2) (p24alpha2) (p25) O14668 TMG1_HUMAN Transmembrane gamma-carboxyglutamic acid protein 1 (Proline-rich gamma- PRRG1 PRGP1 218 carboxyglutamic acid protein 1) (Proline-rich Gla protein 1) TMG1 Q96BF3 TMIG2_HUMAN Transmembrane and immunoglobulin domain-containing protein 2 (CD28 homolog) TMIGD2 CD28H 282 (Immunoglobulin and proline-rich receptor 1) (IGPR-1) IGPR1 UNQ3059/PRO9879 P43489 TNR4_HUMAN Tumor necrosis factor receptor superfamily member 4 (ACT35 antigen) (OX40L receptor) TNFRSF4 TXGP1L 111 (TAX transcriptionally-activated glycoprotein 1 receptor) (CD antigen CD134) P25942 TNR5_HUMAN Tumor necrosis factor receptor superfamily member 5 (B-cell surface antigen CD40) CD40 TNFRSF5 277 (Bp50) (CD40L receptor) (CDw40) (CD antigen CD40) P25445 TNR6_HUMAN Tumor necrosis factor receptor superfamily member 6 (Apo-1 antigen) (Apoptosis- FAS APT1 FAS1 335 mediating surface antigen FAS) (FASLG receptor) (CD antigen CD95) TNFRSF6 O14763 TR10B_HUMAN Tumor necrosis factor receptor superfamily member 10B (Death receptor 5) (TNF-related TNFRSF10B DR5 440 apoptosis-inducing ligand receptor 2) (TRAIL receptor 2) (TRAIL-R2) (CD antigen CD262) KILLER TRAILR2 TRICK2 ZTNFR9 UNQ160/PRO186 Q8TB96 TIP_HUMAN T-cell immunomodulatory protein (Protein TIP) (Integrin-alpha FG-GAP repeat-containing ITFG1 LNKN-1 TIP 612 protein 1) (Linkin) CDA08 O00206 TLR4_HUMAN Toll-like receptor 4 (hToll) (CD antigen CD284) TLR4 839 Q6P9G4 TM154_HUMAN Transmembrane protein 154 TMEM154 183 Q9BXS4 TMM59_HUMAN Transmembrane protein 59 (Liver membrane-bound protein) TMEM59 C1orf8 323 HSPC001 UNQ169/PRO195 Q9NP84 TNR12_HUMAN Tumor necrosis factor receptor superfamily member 12A (Fibroblast growth factor- TNFRSF12A FN14 129 inducible immediate-early response protein 14) (FGF-inducible 14) (Tweak-receptor) (TweakR) (CD antigen CD266) Q9Y5U5 TNR18_HUMAN Tumor necrosis factor receptor superfamily member 18 (Activation-inducible TNFR family TNFRSF18 AITR 241 receptor) (Glucocorticoid-induced TNFR-related protein) (CD antigen CD357) GITR UNQ319/PRO364 P20333 TNR1B_HUMAN Tumor necrosis factor receptor superfamily member 1B (Tumor necrosis factor receptor TNFRSF1B TNFBR 461 2) (TNF-R2) (Tumor necrosis factor receptor type II) (TNF-RII) (TNFR-II) (p75) (p80 TNF- TNFR2 alpha receptor) (CD antigen CD120b) (Etanercept) [Cleaved into: Tumor necrosis factor receptor superfamily member 1b, membrane form; Tumor necrosis factor-binding protein 2 (TBP-2) (TBPII)] Q9UBN6 TR10D_HUMAN Tumor necrosis factor receptor superfamily member 10D (Decoy receptor 2) (DcR2) TNFRSF10D DCR2 386 (TNF-related apoptosis-inducing ligand receptor 4) (TRAIL receptor 4) (TRAIL-R4) TRAILR4 TRUNDD (TRAIL receptor with a truncated death domain) (CD antigen CD264) UNQ251/PRO288 Q9NZC2 TREM2_HUMAN Triggering receptor expressed on myeloid cells 2 (TREM-2) (Triggering receptor TREM2 230 expressed on monocytes 2) A6NFA1 TIKI2_HUMAN Metalloprotease TIKI2 (EC 3.4.—.—) (Heart, kidney and adipose-enriched transmembrane TRABD2B HKAT 517 protein homolog) (TRAB domain-containing protein 2B) TIKI2 Q9NYK1 TLR7_HUMAN Toll-like receptor 7 TLR7 1049 UNQ248/PRO285 Q9NR96 TLR9_HUMAN Toll-like receptor 9 (CD antigen CD289) TLR9 1032 UNQ5798/PRO19605 A2RRL7 TM213_HUMAN Transmembrane protein 213 TMEM213 107 Q9P0T7 TMEM9_HUMAN Transmembrane protein 9 (Dermal papilla-derived protein 4) TMEM9 DERP4 183 TMEM9A HSPC186 PSEC0012 UNQ631/PRO1248 A2RUT3 TMM89_HUMAN Transmembrane protein 89 TMEM89 159 Q9H3N1 TMX1_HUMAN Thioredoxin-related transmembrane protein 1 (Thioredoxin domain-containing protein 1) TMX1 TMX TXNDC 280 (Transmembrane Trx-related protein) TXNDC1 PSEC0085 UNQ235/PRO268 Q92956 TNR14_HUMAN Tumor necrosis factor receptor superfamily member 14 (Herpes virus entry mediator A) TNFRSF14 HVEA 283 (Herpesvirus entry mediator A) (HveA) (Tumor necrosis factor receptor-like 2) (TR2) (CD HVEM antigen CD270) UNQ329/PRO509 Q9NS68 TNR19_HUMAN Tumor necrosis factor receptor superfamily member 19 (TRADE) (Toxicity and JNK TNFRSF19 TAJ 423 inducer) TROY UNQ1888/PRO4333 P19438 TNR1A_HUMAN Tumor necrosis factor receptor superfamily member 1A (Tumor necrosis factor receptor TNFRSF1A TNFAR 455 1) (TNF-R1) (Tumor necrosis factor receptor type I) (TNF-RI) (TNFR-I) (p55) (p60) (CD TNFR1 antigen CD120a) [Cleaved into: Tumor necrosis factor receptor superfamily member 1A, membrane form; Tumor necrosis factor-binding protein 1 (TBPI)] Q93038 TNR25_HUMAN Tumor necrosis factor receptor superfamily member 25 (Apo-3) (Apoptosis-inducing TNFRSF25 APO3 417 receptor AIR) (Apoptosis-mediating receptor DR3) (Apoptosis-mediating receptor DDR3 DR3 TRAMP) (Death receptor 3) (Lymphocyte-associated receptor of death) (LARD) (Protein TNFRSF12 WSL WSL) (Protein WSL-1) WSL1 UNQ455/PRO779 P0DKB5 TPBGL_HUMAN Trophoblast glycoprotein-like TPBGL 382 Q9BX59 TPSNR_HUMAN Tapasin-related protein (TAPASIN-R) (TAP-binding protein-like) (TAP-binding protein- TAPBPL 468 related protein) (TAPBP-R) (Tapasin-like) O60603 TLR2_HUMAN Toll-like receptor 2 (Toll/interleukin-1 receptor-like protein 4) (CD antigen CD282) TLR2 TIL4 784 Q6UXF1 TM108_HUMAN Transmembrane protein 108 TMEM108 575 KIAA1690 UNQ1875/PRO4318 Q8IV31 TM139_HUMAN Transmembrane protein 139 TMEM139 216 UNQ1932/PRO4407 A6NLX4 TM210_HUMAN Transmembrane protein 210 TMEM210 147 Q9Y3Q3 TMED3_HUMAN Transmembrane emp24 domain-containing protein 3 (Membrane protein p24B) (p24 TMED3 C15orf22 217 family protein gamma-4) (p24gamma4) (p26) UNQ5357/PRO1078 O14669 TMG2_HUMAN Transmembrane gamma-carboxyglutamic acid protein 2 (Praline-rich gamma- PRRG2 PRGP2 202 carboxyglutamic acid protein 2) (Proline-rich Gla protein 2) TMG2 Q9BZD7 TMG3_HUMAN Transmembrane gamma-carboxyglutamic acid protein 3 (Proline-rich gamma- PRRG3 PRGP3 231 carboxyglutamic acid protein 3) (Proline-rich Gla protein 3) TMG3 Q9Y320 TMX2_HUMAN Thioredoxin-related transmembrane protein 2 (Cell proliferation-inducing gene 26 protein) TMX2 TXNDC14 296 (Thioredoxin domain-containing protein 14) CGI-31 My009 PIG26 PSEC0045 UNQ237/PRO270 P36941 TNR3_HUMAN Tumor necrosis factor receptor superfamily member 3 (Lymphotoxin-beta receptor) LTBR D12S370 435 (Tumor necrosis factor C receptor) (Tumor necrosis factor receptor 2-related protein) TNFCR TNFR3 (Tumor necrosis factor receptor type III) (TNF-RIII) (TNFR-III) TNFRSF3 Q13641 TPBG_HUMAN Trophoblast glycoprotein (5T4 oncofetal antigen) (5T4 oncofetal trophoblast glycoprotein) TPBG 5T4 420 (5T4 oncotrophoblast glycoprotein) (M6P1) (Wnt-activated inhibitory factor 1) (WAIF1) P40238 TPOR_HUMAN Thrombopoietin receptor (TPO-R) (Myeloproliferative leukemia protein) (Proto-oncogene MPL TPOR 635 c-MpI) (CD antigen CD110) P07204 TRBM_HUMAN Thrombomodulin (TM) (Fetomodulin) (CD antigen CD141) THBD THRM 575 Q5T2D2 TRML2_HUMAN Trem-like transcript 2 protein (TLT-2) (Triggering receptor expressed on myeloid cells-like TREML2 C6orf76 321 protein 2) TLT2 UNQ6268/PRO20473 Q6UXZ0 TMIG1_HUMAN Transmembrane and immunoglobulin domain-containing protein 1 TMIGD1 TMIGD 262 UNQ9372/PRO34164 Q86YD3 TMM25_HUMAN Transmembrane protein 25 TMEM25 366 UNQ2531/PRO6030 Q6P7N7 TMM81_HUMAN Transmembrane protein 81 TMEM81 255 UNQ2788/PRO7178 Q3KNT9 TMM95_HUMAN Transmembrane protein 95 TMEM95 176 UNQ9390/PRO34281 Q9H1E5 TMX4_HUMAN Thioredoxin-related transmembrane protein 4 (Thioredoxin domain-containing protein 13) TMX4 KIAA1162 349 TXNDC13 PSEC0095 UNQ475/PRO938 Q9Y6Q6 TNR11_HUMAN Tumor necrosis factor receptor superfamily member 11A (Osteoclast differentiation factor TNFRSF11A RANK 616 receptor) (ODFR) (Receptor activator of NF-KB) (CD antigen CD265) Q86YW5 TRML1_HUMAN Trem-like transcript 1 protein (TLT-1) (Triggering receptor expressed on myeloid cells-like TREML1 TLT1 311 protein 1) UNQ1825/PRO3438 P08138 TNR16_HUMAN Tumor necrosis factor receptor superfamily member 16 (Gp80-LNGFR) (Low affinity NGFR TNFRSF16 427 neurotrophin receptor p75NTR) (Low-affinity nerve growth factor receptor) (NGF receptor) (P75ICD) (CD antigen CD271) O75509 TNR21_HUMAN Tumor necrosis factor receptor superfamily member 21 (Death receptor 6) (CD antigen TNFRSF21 DR6 655 CD358) UNQ437/PRO868 P28908 TNR8_HUMAN Tumor necrosis factor receptor superfamily member 8 (CD30L receptor) (Ki-1 antigen) TNFRSF8 CD30 595 (Lymphocyte activation antigen CD30) (CD antigen CD30) D1S166E O00220 TR10A_HUMAN Tumor necrosis factor receptor superfamily member 10A (Death receptor 4) (TNF-related TNFRSF10A APO2 468 apoptosis-inducing ligand receptor 1) (TRAIL receptor 1) (TRAIL-R1) (CD antigen CD261) DR4 TRAILR1 Q9NP99 TREM1_HUMAN Triggering receptor expressed on myeloid cells 1 (TREM-1) (Triggering receptor TREM1 234 expressed on monocytes 1) (CD antigen CD354) O15533 TPSN_HUMAN Tapasin (TPN) (TPSN) (NGS-17) (TAP-associated protein) (TAP-binding protein) TAPBP NGS17 448 TAPA Q969Z4 TR19L_HUMAN Tumor necrosis factor receptor superfamily member 19L (Receptor expressed in RELT TNFRSF19L 430 lymphoid tissues) Q7L0X0 TRIL_HUMAN TLR4 interactor with leucine rich repeats (Leucine-rich repeat-containing protein TRIL KIAA0644 811 KIAA0644) Q5BVD1 TTMP_HUMAN TPA-induced transmembrane protein TTMP C3orf52 217 Q96J42 TXD15_HUMAN Thioredoxin domain-containing protein 15 TXNDC15 C5orf14 360 UNQ335/PRO534 Q9P2J2 TUTLA_HUMAN Protein turtle homolog A (Immunoglobulin superfamily member 9A) (IgSF9A) IGSF9 IGSF9A 1179 KIAA1355 NRT1 Q9UPX0 TUTLB_HUMAN Protein turtle homolog B (Immunoglobulin superfamily member 9B) (IgSF9B) IGSF9B KIAA1030 1349 Q3SY77 UD3A2_HUMAN UDP-glucuronosyltransferase 3A2 (UDPGT 3A2) (EC 2.4.1.17) UGT3A2 PSEC0073 523 UNQ842/PRO1780 P14679 TYRO_HUMAN Tyrosinase (EC 1.14.18.1) (LB24-AB) (Monophenol monooxygenase) (SK29-AB) (Tumor TYR 529 rejection antigen AB) P40126 TYRP2_HUMAN L-dopachrome tautomerase (DCT) (DT) (EC 5.3.3.12) (L-dopachrome Delta-isomerase) DCT TYRP2 519 (Tyrosinase-related protein 2) (TRP-2) (TRP2) O95185 UNC5C_HUMAN Netrin receptor UNC5C (Protein unc-5 homolog 3) (Protein unc-5 homolog C) UNC5C UNC5H3 931 Q06418 TYRO3_HUMAN Tyrosine-protein kinase receptor TYRO3 (EC 2.7.10.1) (Tyrosine-protein kinase BYK) TYRO3 BYK DTK 890 (Tyrosine-protein kinase DTK) (Tyrosine-protein kinase RSE) (Tyrosine-protein kinase RSE SKY TIF SKY) (Tyrosine-protein kinase TIP) Q9Y4X1 UD2A1_HUMAN UDP-glucuronosyltransferase 2A1 (UDPGT 2A1) (EC 2.4.1.17) UGT2A1 UGT2A2 527 Q9BT76 UPK3B_HUMAN Uroplakin-3b (UP3b) (Uroplakin IIIb) (UPIIIb) (p35) UPK3B 320 O43914 TYOBP_HUMAN TYRO protein tyrosine kinase-binding protein (DNAX-activation protein 12) (Killer- TYROBP DAP12 113 activating receptor-associated protein) (KAR-associated protein) KARAP Q6NUS8 UD3A1_HUMAN UDP-glucuronosyltransferase 3A1 (UDPGT 3A1) (EC 2.4.1.17) UGT3A1 523 O00526 UPK2_HUMAN Uroplakin-2 (UP2) (Uroplakin II) (UPII) UPK2 184 B0FP48 UPK3L_HUMAN Uroplakin-3b-like protein UPK3BL UPLP 263 P17643 TYRP1_HUMAN 5,6-dihydroxyindole-2-carboxylicacid oxidase (DHICA oxidase) (EC 1.14.18.—) (Catalase TYRP1 CAS2 TYRP 537 B) (Glycoprotein 75) (Melanoma antigen gp75) (Tyrosinase-related protein 1) (TRP) TYRRP (TRP-1) (TRP1) O75631 UPK3A_HUMAN Uroplakin-3a (UP3a) (Uroplakin III) (UPIII) UPK3A UPK3 287 O75445 USH2A_HUMAN Usherin (Usher syndrome type IIa protein) (Usher syndrome type-2A protein) USH2A 5202 P30530 UFO_HUMAN Tyrosine-protein kinase receptor UFO (EC 2.7.10.1) (AXL oncogene) AXL UFO 894 Q8IZJ1 UNC5B_HUMAN Netrin receptor UNC5B (Protein unc-5 homolog 2) (Protein unc-5 homolog B) (p53- UNC5B P53RDL1 945 regulated receptor for death and life protein 1) (p53RDL1) UNC5H2 UNQ1883/PRO4326 Q6UWM9 UD2A3_HUMAN UDP-glucuronosyltransferase 2A3 (UDPGT 2A3) (EC 2.4.1.17) UGT2A3 527 UNQ2559/PRO6239 Q5DID0 UROL1_HUMAN Uromodulin-like 1 (Olfactorin) UMODL1 1318 Q6ZN44 UNC5A_HUMAN Netrin receptor UNC5A (Protein unc-5 homolog 1) (Protein unc-5 homolog A) UNC5A KIAA1976 842 UNC5H1 Q6UXZ4 UNC5D_HUMAN Netrin receptor UNC5D (Protein unc-5 homolog 4) (Protein unc-5 homolog D) UNC5D KIAA1777 953 UNC5H4 UNQ6012/PRO34692 P19320 VCAM1_HUMAN Vascular cell adhesion protein 1 (V-CAM 1) (VCAM-1) (INCAM-100) (CD antigen CD106) VCAM1 L1CAM 739 P35916 VGFR3_HUMAN Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC 2.7.10.1) (Fms-like tyrosine FLT4 VEGFR3 1363 kinase 4) (FLT-4) (Tyrosine-protein kinase receptor FLT4) Q7Z7D3 VTCN1_HUMAN V-set domain-containing T-cell activation inhibitor 1 (B7 homolog 4) (B7-H4) (B7h.5) VTCN1 B7H4 282 (Immune costimulatory protein B7-H4) (Protein B7S1) (T-cell costimulatory molecule B7x) UNQ659/PRO1291 Q6EMK4 VASN_HUMAN Vasorin (Protein slit-like 2) VASN SLITL2 673 UNQ314/PRO357/ PRO1282 Q96AW1 VOPP1_HUMAN Vesicular, overexpressed in cancer, prosurvival protein 1 (EGFR-coamplified and VOPP1 ECOP 172 overexpressed protein) (ECop) (Glioblastoma-amplified secreted protein) (Putative NF- GASP kappa-B-activating protein 055N) P17948 VGFR1_HUMAN Vascular endothelial growth factor receptor 1 (VEGFR-1) (EC 2.7.10.1) (Fms-like tyrosine FLT1 FLT FRT 1338 kinase 1) (FLT-1) (Tyrosine-protein kinase FRT) (Tyrosine-protein kinase receptor FLT) VEGFR1 (FLT) (Vascular permeability factor receptor) Q9H7M9 VISTA_HUMAN V-type immunoglobulin domain-containing suppressor of T-cell activation (Platelet C10orf54 SISP1 311 receptor Gi24) (Stress-induced secreted protein-1) (Sisp-1) (V-set domain-containing VISTA PP2135 immunoregulatory receptor) UNQ730/PRO1412 Q86VR7 VS10L_HUMAN V-set and immunoglobulin domain-containing protein 10-like VSIG10L 867 Q96IQ7 VSIG2_HUMAN V-set and immunoglobulin domain-containing protein 2 (Cortical thymocyte-like protein) VSIG2 CTH CTXL 327 (CT-like protein) UNQ2770/PRO7154 Q5VU13 VSIG8_HUMAN V-set and immunoglobulin domain-containing protein 8 VSIG8 C1orf204 414 P78423 X3CL1_HUMAN Fractalkine (C-X3-C motif chemokine 1) (CX3C membrane-anchored chemokine) CX3CL1 FKN NTT 397 (Neurotactin) (Small-inducible cytokine D1) [Cleaved into: Processed fractalkine] SCYD1 A-152E5.2 P35968 VGFR2_HUMAN Vascular endothelial growth factor receptor 2 (VEGFR-2) (EC 2.7.10.1) (Fetal liver kinase KDR FLK1 VEGFR2 1356 1) (FLK-1) (Kinase insert domain receptor) (KDR) (Protein-tyrosine kinase receptor flk-1) (CD antigen CD309) Q8N0Z9 VSI10_HUMAN V-set and immunoglobulin domain-containing protein 10 VSIG10 540 Q8IW00 VSTM4_HUMAN V-set and transmembrane domain-containing protein 4 [Cleaved into: Peptide Lv] VSTM4 C10orf72 320 P55808 XG_HUMAN Glycoprotein Xg (Protein PBDX) XG PBDX 180 P98155 VLDLR_HUMAN Very low-density lipoprotein receptor (VLDL receptor) (VLDL-R) VLDLR 873 Q86XK7 VSIG1_HUMAN V-set and immunoglobulin domain-containing protein 1 (Cell surface A33 antigen) VSIG1 GPA34 387 (Glycoprotein A34) Q9Y279 VSIG4_HUMAN V-set and immunoglobulin domain-containing protein 4 (Protein Z39Ig) VSIG4 CRIg Z39IG 399 UNQ317/PRO362 A6NLU5 VTM2B_HUMAN V-set and transmembrane domain-containing protein 2B VSTM2B 285 A8MXK1 VSTM5_HUMAN V-set and transmembrane domain-containing protein 5 VSTM5 C11orf90 200 Q8N1Y9 YI025_HUMAN Putative uncharacterized protein FLJ37218 231 P60852 ZP1_HUMAN Zona pellucida sperm-binding protein 1 (Zona pellucida glycoprotein 1) (Zp-1) [Cleaved ZP1 638 into: Processed zona pellucida sperm-binding protein 1] Q05996 ZP2_HUMAN Zona pellucida sperm-binding protein 2 (Zona pellucida glycoprotein 2) (Zp-2) (Zona ZP2 ZPA 745 pellucida protein A) [Cleaved into: Processed zona pellucida sperm-binding protein 2] Q9Y493 ZAN_HUMAN Zonadhesin ZAN 2812 Q9ULT6 ZNRF3_HUMAN E3 ubiquitin-protein ligase ZNRF3 (EC 6.3.2.—) (RING finger protein 203) (Zinc/RING ZNRF3 KIAA1133 936 finger protein 3) RNF203 Q8TCW7 ZPLD1_HUMAN Zona pellucida-like domain-containing protein 1 (ZP domain-containing protein 1) ZPLD1 415 Q8WWF5 ZNRF4_HUMAN E3 ubiquitin-protein ligase ZNRF4 (EC 6.3.2.—) (Nixin) (RING finger protein 204) ZNRF4 RNF204 429 (Zinc/RING finger protein 4) P21754 ZP3_HUMAN Zona pellucida sperm-binding protein 3 (Sperm receptor) (ZP3A/ZP3B) (Zona pellucida ZP3 ZP3A ZP3B 424 glycoprotein 3) (Zp-3) (Zona pellucida protein C) [Cleaved into: Processed zona pellucida ZPC sperm-binding protein 3] Q12836 ZP4_HUMAN Zona pellucida sperm-binding protein 4 (Zona pellucida glycoprotein 4) (Zp-4) (Zona ZP4 ZPB 540 pellucida protein B) [Cleaved into: Processed zona pellucida sperm-binding protein 4] K9MUJ5 K9MUJ5_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 K9MUQ3 K9MUQ3_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 D3DNA1 D3DNA1_HUMAN Integrin beta ITGB5 hCG_17803 691 K9MTL8 K9MTL8_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 K9MSZ3 K9MSZ3_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 K9MT91 K9MT91_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 D3DSM0 D3DSM0_HUMAN Integrin beta ITGB2 hCG_401305 712 K9MT22 K9MT22_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 K9MUK7 K9MUK7_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 D0EWT7 D0EWT7_HUMAN Toll-like receptor 4 (Fragment) TLR-4 TLR4 169 G3V1J9 G3V1J9_HUMAN Transmembrane emp24 domain-containing protein 3 (Transmembrane emp24 protein TMED3 hCG_24828 146 transport domain containing 3, isoform CRA_b) L7RT22 L7RT22_HUMAN Integrin beta ITGB5 799 G3V1W8 G3V1W8_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30) ACVRL1 517 hCG_37967 A3QNQ0 A3QNQ0_HUMAN TGF-beta receptor type-2 (TGFR-2) (EC 2.7.11.30) (TGF-beta type II receptor) TGFBR2 567 (Transforming growth factor-beta receptor type II) hCG_1997782 B4E1S6 B4E1S6_HUMAN Syndecan SDC4 hCG_38363 126 A0A024R8T0 A0A024R8T0_HUMAN Integrin beta ITGB4 hCG_27538 1822 D3DPA4 D3DPA4_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30) ACVR1 509 hCG_1811747 A0A024R6I3 A0A024R6I3_HUMAN Testicular tissue protein Li 206 (Transmembrane emp24-like trafficking protein 10 TMED10 219 (Yeast), isoform CRA_a) hCG_22348 A0A024RB01 A0A024RB01_HUMAN Integrin, alpha 5 (Fibronectin receptor, alpha polypeptide), isoform CRA_b ITGA5 hCG_21939 1098 A0A024R7M0 A0A024R7M0_HUMAN Transmembrane emp24 protein transport domain containing 9, isoform CRA_a TMED9 hCG_41592 235 B7Z4L4 B7Z4L4_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) RPN1 435 A0A024DBF0 A0A024DBF0_HUMAN Integrin beta (Fragment) ITGB2 80 A0A024RDA0 A0A024RDA0_HUMAN V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, isoform CRA_a KIT hCG_22160 976 Q9BUG9 Q9BUG9_HUMAN Integrin beta ITGB8 hCG_37311 439 D3DPN2 D3DPN2_HUMAN Syndecan SDC3 hCG_15913 384 A0A024RC30 A0A024RC30_HUMAN Desmoglein 3 (Pemphigus vulgaris antigen), isoform CRA_a DSG3 hCG_25473 999 E9PBI9 E9PBI9_HUMAN Syndecan SDC2 172 A0A024RC29 A0A024RC29_HUMAN Desmocollin 3, isoform CRA_b DSC3 896 hCG_2022649 X5D8X5 X5D8X5_HUMAN Cadherin 10 type 2 isoform A (Cadherin 10, type 2 (T2-cadherin)) (Fragment) CDH10 hCG_36812 788 B2R627 B2R627_HUMAN cDNA, FLJ92752, highly similar to Homo sapiens integrin, alpha 5 (fibronectin receptor, 1049 alphapolypeptide) (ITGA5), mRNA Q6FHT8 Q6FHT8_HUMAN RNP24 protein (Transmembrane emp24 domain trafficking protein 2, isoform CRA_a) RNP24 TMED2 201 (cDNA, FLJ93436, Homo sapiens coated vesicle membrane protein (RNP24), mRNA) hCG_1743563 B4DTY8 B4DTY8_HUMAN cDNA FLJ61587, highly similar to Integrin alpha-1 (Fragment) 1173 Q96CZ9 Q96CZ9_HUMAN Cadherin 11, type 2, OB-cadherin (Osteoblast) (Cadherin 11, type 2, OB-cadherin CDH11 hCG_26636 796 (Osteoblast), isoform CRA_c) A0A024RD88 A0A024RD88_HUMAN Kinase insert domain receptor (A type III receptor tyrosine kinase), isoform CRA_a KDR hCG_31572 1356 A0A024R8N2 A0A024R8N2_HUMAN Integrin beta ITGB4 hCG_27538 1875 A0A024R2B2 A0A024R2B2_HUMAN Cadherin 7, type 2, isoform CRA_a CDH7 hCG_32903 785 E7EQW5 E7EQW5_HUMAN Integrin beta (Fragment) ITGB1 163 Q59F03 Q59F03_HUMAN Integrin alpha 3 isoform b, variant (Fragment) 749 A0A0G2JRA4 A0A0G2JRA4_HUMAN Cadherin-4 (Fragment) CDH4 566 U3KQ84 U3KQ84_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit DDOST 155 (Oligosaccharyl transferase 48 kDa subunit) (EC 2.4.99.18) (Fragment) B4E2C1 B4E2C1_HUMAN cDNA FLJ57776, highly similar to Transmembrane emp24 domain-containing protein 7 136 J3KRI5 J3KRI5_HUMAN Cadherin-8 CDH8 744 E9PD35 E9PD35_HUMAN Vascular endothelial growth factor receptor 3 FLT4 1306 E7EQ72 E7EQ72_HUMAN Transmembrane emp24 domain-containing protein 2 (Fragment) TMED2 166 D2JYI3 D2JYI3_HUMAN Toll-like receptor 4 (Fragment) TLR4 121 J3KT08 J3KT08_HUMAN Uncharacterized protein (Fragment) 172 A8K0L1 A8K0L1_HUMAN cDNA FLJ77485, highly similar to Homo sapiens cadherin-like 24 (CDH24), transcript 781 variant 2, mRNA D2JYI2 D2JYI2_HUMAN Toll-like receptor 4 (Fragment) TLR4 122 E7EP60 E7EP60_HUMAN Integrin alpha-4 (Fragment) ITGA4 614 Q59H01 Q59H01_HUMAN Protocadherin gamma subfamily A, 7 isoform 1 variant (Fragment) 895 D2JYI5 D2JYI5_HUMAN Toll-like receptor 4 (Fragment) TLR4 124 J3KNV4 J3KNV4_HUMAN Integrin alpha-7 ITGA7 1131 H3BM21 H3BM21_HUMAN Integrin beta (Fragment) 787 B4DN28 B4DN28_HUMAN cDNA FLJ54639, highly similar to Integrin alpha-8 (Fragment) 1048 A0A0S2Z4U3 A0A0S2Z4U3_HUMAN Syndecan (Fragment) SDC3 370 B4DL99 B4DL99_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) 581 B4DLF0 B4DLF0_HUMAN cDNA FLJ50795, highly similar to Cadherin-3 774 Q6P4R2 Q6P4R2_HUMAN Protocadherin alpha subfamily C, 2 PCDHAC2 1007 V9GYZ1 V9GYZ1_HUMAN Integrin beta (Fragment) ITGB5 139 D1CS55 D1CS55_HUMAN Toll-like receptor 4 TLR4 839 D0EWT8 D0EWT8_HUMAN Toll-like receptor 4 (Fragment) TLR-4 TLR4 169 A8K2C5 A8K2C5_HUMAN cDNA FLJ78159, highly similar to Homo sapiens cadherin 20, type 2 (CDH20), mRNA 801 Q59GD1 Q59GD1_HUMAN Protocadherin gamma subfamily A, 6 isoform 1 variant (Fragment) 950 L7RSL3 L7RSL3_HUMAN Fms-related tyrosine kinase 1 (Vascular endothelial growth factor/vascular permeability FLT1 1338 factor receptor) A8K8T0 A8K8T0_HUMAN cDNA FLJ78760, highly similar to Homo sapiens integrin, alpha 11 (ITGA11), transcript 1188 variant 1, mRNA Q4VAU9 Q4VAU9_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30) ACVR2B 303 Q5T3E5 Q5T3E5_HUMAN Integrin beta (Fragment) ITGB1 89 E5RK25 E5RK25_HUMAN Integrin beta (Fragment) ITGB2 160 A8KAM8 A8KAM8_HUMAN Platelet-derived growth factor receptor beta (PDGF-R-beta) (PDGFR-beta) (EC 2.7.10.1) 1106 (Beta platelet-derived growth factor receptor) (Beta-type platelet-derived growth factor receptor) E9PQJ2 E9PQJ2_HUMAN Integrin beta (Fragment) ITGB1 104 B4E2S6 B4E2S6_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30) 397 A0A087WXP3 A0A087WXP3_HUMAN Integrin beta ITGB6 693 A8K0L9 A8K0L9_HUMAN cDNA FLJ76999, highly similar to Homo sapiens cadherin-like 22 (CDH22), mRNA 828 D2JYI1 D2JYI1_HUMAN TGF-beta receptor type-2 (TGFR-2) (EC 2.7.11.30) (TGF-beta type II receptor) TGFBR2 592 (Transforming growth factor-beta receptor type II) B7ZLD8 B7ZLD8_HUMAN Integrin beta ITGB4 1752 L7UW06 L7UW06_HUMAN Integrin beta ITGB3 470 B4E3M0 B4E3M0_HUMAN cDNA FLJ58807, highly similar to Integrin alpha-11 650 B4DNJ5 B4DNJ5_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) 378 Q96HX3 Q96HX3_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) 568 (Fragment) X5DNG6 X5DNG6_HUMAN Cadherin 10 type 2 isoform B (Fragment) CDH10 786 B7Z5H2 B7Z5H2_HUMAN Syndecan 172 F8VNX4 F8VNX4_HUMAN Integrin beta (Fragment) ITGB7 158 B4DPP4 B4DPP4_HUMAN cDNA FLJ56646, highly similar to Transmembrane emp24 domain-containing protein 9 121 B2RCN5 B2RCN5_HUMAN cDNA, FLJ96176, highly similar to Homo sapiens cadherin 4, type 1, R-cadherin (retinal) 916 (CDH4), mRNA G3V2K7 G3V2K7_HUMAN Transmembrane emp24 domain-containing protein 10 TMED10 153 A8K6T3 A8K6T3_HUMAN cDNA FLJ78674, highly similar to Homo sapiens desmocollin type 4 896 E9PLR6 E9PLR6_HUMAN Integrin beta (Fragment) ITGB1 143 D3XNU5 D3XNU5_HUMAN E-cadherin 1 CDH1 882 B4E2A1 B4E2A1_HUMAN cDNA FLJ54402, highly similar to Integrin alpha-10 1095 C9JPK5 C9JPK5_HUMAN Integrin beta (Fragment) ITGB1 98 B2R8A2 B2R8A2_HUMAN cDNA, FLJ93804, highly similar to Homo sapiens gp25L2 protein (HSGP25L2G), mRNA 214 L7UUZ7 L7UUZ7_HUMAN Integrin beta ITGB3 788 Q53EP4 Q53EP4_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) 607 (Fragment) Q59H32 Q59H32_HUMAN Protocadherin gamma subfamily A, 3 isoform 1 variant (Fragment) 961 K9MUK4 K9MUK4_HUMAN Toll-like receptor 4 (Fragment) TLR4 138 B3KMS6 B3KMS6_HUMAN cDNA FLJ12486 fis, clone NT2RM2000566, highly similar to Integrin alpha-7 973 B4E045 B4E045_HUMAN cDNA FLJ59131, highly similar to Integrin alpha-4 174 B7ZLD5 B7ZLD5_HUMAN Integrin beta ITGB4 1752 Q59EA3 Q59EA3_HUMAN Cadherin 5, type 2 preproprotein variant (Fragment) 807 E7ESK6 E7ESK6_HUMAN Syndecan SDC2 165 B4DTP0 B4DTP0_HUMAN cDNA FLJ51087, highly similar to Cadherin-5 525 B4E3N0 B4E3N0_HUMAN Integrin beta 628 A7U833 A7U833_HUMAN Integrin beta (Fragment) ITGB3 65 A0A024R8K7 A0A024R8K7_HUMAN Integrin beta ITGB4 hCG_27538 1752 H7C580 H7C580_HUMAN Integrin beta (Fragment) ITGB5 79 H0YA32 H0YA32_HUMAN Integrin alpha-3 (Fragment) ITGA3 84 Q59H14 Q59H14_HUMAN PREDICTED: integrin, alpha D variant (Fragment) 1177 E9PDS3 E9PDS3_HUMAN Integrin alpha-9 ITGA9 632 B2R6U9 B2R6U9_HUMAN Delta-like protein 1218 B4E0R1 B4E0R1_HUMAN Integrin beta 700 A5YM53 A5YM53_HUMAN ITGAV protein ITGAV 1048 Q6IBR0 Q6IBR0_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) RPN1 607 B4DP27 B4DP27_HUMAN cDNA FLJ52153, highly similar to Transmembrane emp24 domain-containing protein 2 169 A0A0U2ZQU7 A0A0U2ZQU7_HUMAN E-cadherin 1 CDH1 882 B4DYQ7 B4DYQ7_HUMAN cDNA FLJ57822, highly similar to Integrin alpha-V 482 B2RAL6 B2RAL6_HUMAN cDNA, FLJ94991, highly similar to Homo sapiens integrin, alpha L (antigen CD11A 1170 (p180), lymphocyte function-associated antigen 1; alpha polypeptide) (ITGAL), mRNA E7ERX5 E7ERX5_HUMAN Integrin beta (Fragment) ITGB1 125 F8WF32 F8WF32_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (EC 2.4.99.18) RPN1 121 B4E0Q2 B4E0Q2_HUMAN cDNA FLJ60208, highly similar to Integrin alpha-4 366 B4DDT0 B4DDT0_HUMAN cDNA FLJ59664, highly similar to Integrin alpha-3 294 B7Z769 B7Z769_HUMAN Integrin beta 228 E9PEE8 E9PEE8_HUMAN Integrin beta ITGB6 746 H7C4W1 H7C4W1_HUMAN Integrin beta (Fragment) ITGB5 263 E9PB77 E9PB77_HUMAN Integrin alpha-2 ITGA2 641 B7Z8B0 B7Z8B0_HUMAN cDNA FLJ50317, highly similar to Integrin alpha-IIb 219 D6RA20 D6RA20_HUMAN Protocadherin alpha-4 PCDHA4 901 Q5T3E6 Q5T3E6_HUMAN Integrin beta (Fragment) ITGB1 136 B4DQ56 B4DQ56_HUMAN Syndecan 192 C9JA99 C9JA99_HUMAN Protocadherin alpha-13 PCDHA13 904 Q9UII7 Q9UII7_HUMAN E-cadherin 901 B3KRT0 B3KRT0_HUMAN cDNA FLJ34857 fis, clone NT2NE2012533, highly similar to Cadherin-12 404 Q8N6H6 Q8N6H6_HUMAN ITGA9 protein 632 A0A0B5HR54 A0A0B5HR54_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30) 509 C9JXX7 C9JXX7_HUMAN Integrin alpha-6 (Fragment) ITGA6 231 B4DLJ5 B4DLJ5_HUMAN cDNA FLJ55716, highly similar to Desmocollin-2 912 V9GZ57 V9GZ57_HUMAN Integrin beta (Fragment) ITGB5 324 Q4LE35 Q4LE35_HUMAN ITGA7 variant protein (Fragment) ITGA7 variant 1200 protein B4DIN4 B4DIN4_HUMAN Syndecan 346 J3KNI6 J3KNI6_HUMAN Integrin beta (Fragment) ITGB2 322 A8K2P8 A8K2P8_HUMAN cDNA FLJ76245, highly similar to Homo sapiens desmocollin 2 (DSC2), transcript variant 901 Dsc2a, mRNA B4DLU2 B4DLU2_HUMAN cDNA FLJ56496, highly similar to Integrin alpha-IIb 521 F5H4M7 F5H4M7_HUMAN Transmembrane emp24 domain-containing protein 3 TMED3 155 D0EWT9 D0EWT9_HUMAN Toll-like receptor 4 (Fragment) TLR-4 TLR4 169 Q6PJE7 Q6PJE7_HUMAN ITGA4 protein (Fragment) ITGA4 617 E7ESP4 E7ESP4_HUMAN Integrin alpha-2 ITGA2 942 B4E277 B4E277_HUMAN cDNA FLJ58873, highly similar to Transmembrane emp24 domain-containing protein 3 155 B4DU18 B4DU18_HUMAN cDNA FLJ51093, highly similar to Cadherin-5 750 B2R9J8 B2R9J8_HUMAN cDNA, FLJ94427, highly similar to Homo sapiens cadherin 20, type 2 (CDH20), mRNA 801 B4E282 B4E282_HUMAN cDNA FLJ52401, highly similar to Integrin alpha-10 1036 F5H6T4 F5H6T4_HUMAN Integrin beta ITGB7 471 G3V2Y2 G3V2Y2_HUMAN Transmembrane emp24 domain-containing protein 7 (Fragment) TMED7 82 B4DDR7 B4DDR7_HUMAN cDNA FLJ54845, highly similar to Transmembrane emp24 domain-containing protein 5 178 A0A087WT05 A0A087WT05_HUMAN Protocadherin gamma-A4 PCDHGA4 962 B4DMA7 B4DMA7_HUMAN cDNA FLJ58514, highly similar to Cadherin-11 779 A0A0U2N547 A0A0U2N547_HUMAN Mast/stem cell growth factor receptor Kit isoform 3 (EC 2.7.10.1) KIT 971 B2R9L8 B2R9L8_HUMAN Delta-like protein 685 E7EVZ9 E7EVZ9_HUMAN Integrin beta (Fragment) ITGB2 166 B4E2B8 B4E2B8_HUMAN Integrin beta 746 F5GX39 F5GX39_HUMAN Transmembrane emp24 domain-containing protein 2 TMED2 116 Q2VP98 Q2VP98_HUMAN Integrin beta (Fragment) ITGB4 644 A0A0S2Z310 A0A0S2Z310_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30) (Fragment) ACVRL1 503 H3BRM2 H3BRM2_HUMAN Integrin beta (Fragment) ITGB7 93 A9X9L0 A9X9L0_HUMAN Desmocollin 2 DSC2 901 B7Z6U6 B7Z6U6_HUMAN Integrin beta 471 B4DT61 B4DT61_HUMAN Syndecan 81 D2JYI4 D2JYI4_HUMAN Toll-like receptor 4 (Fragment) TLR4 124 E5RIG7 E5RIG7_HUMAN Integrin beta (Fragment) ITGB2 120 E5RFI0 E5RFI0_HUMAN Integrin beta (Fragment) ITGB2 70 B7Z506 B7Z506_HUMAN Integrin beta 626 B4DTY9 B4DTY9_HUMAN Integrin beta 751 G3V2C6 G3V2C6_HUMAN Integrin alpha-7 (Fragment) ITGA7 153 Q6PJ75 Q6PJ75_HUMAN Integrin beta (Fragment) ITGB2 758 B4DDX0 B4DDX0_HUMAN cDNA FLJ59843, highly similar to Integrin alpha-X 264 A9X9K9 A9X9K9_HUMAN Desmocollin 2 DSC2 901 H3BN02 H3BN02_HUMAN Integrin alpha-X ITGAX 1169 A0A024RAD5 A0A024RAD5_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit DDOST 456 (Oligosaccharyl transferase 48 kDa subunit) (EC 2.4.99.18) hCG_38871 A0A0C4DGS1 A0A0C4DGS1_HUMAN Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit DDOST 439 (Oligosaccharyl transferase 48 kDa subunit) (EC 2.4.99.18) B4DFP0 B4DFP0_HUMAN cDNA FLJ57804, highly similar to Cadherin-9 382 Q53GF9 Q53GF9_HUMAN Full-length cDNA 5-PRIME end of clone CSODF013YM24 of Fetal brain of Homo sapiens 225 (Human) variant (Fragment) A8K2N5 A8K2N5_HUMAN Integrin beta 788 E7EUI6 E7EUI6_HUMAN Integrin beta (Fragment) ITGB1 152 Q4KMR2 Q4KMR2_HUMAN Delta-like protein JAG1 1218 Q59FA8 Q59FA8_HUMAN Integrin alpha-IIb variant (Fragment) 551 J3QQL2 J3QQL2_HUMAN Integrin beta (Fragment) ITGB4 114 L7RXH0 L7RXH0_HUMAN Integrin, alpha V ITGAV 1048 A0A0A6YYA0 A0A0A6YYA0_HUMAN Protein TMED7-TICAM2 TMED7-TICAM2 188 B4DL12 B4DL12_HUMAN cDNA FLJ53754, highly similar to Transmembrane emp24 domain-containing protein 10 177 B1AKT3 B1AKT3_HUMAN Transmembrane emp24 domain-containing protein 5 TMED5 162 H7C5U2 H7C5U2_HUMAN Integrin beta (Fragment) ITGB5 401 F8W7F7 F8W7F7_HUMAN Transmembrane emp24 domain-containing protein 4 TMED4 178 Q59H50 Q59H50_HUMAN Integrin beta (Fragment) 475 H3BUU9 H3BUU9_HUMAN Cadherin-11 CDH11 670 B4E0H8 B4E0H8_HUMAN cDNA FLJ60385, highly similar to Integrin alpha-3 1037 A8K6A5 A8K6A5_HUMAN cDNA FLJ77742, highly similar to Homo sapiens integrin, alpha 5 (fibronectin receptor, 1049 alpha polypeptide), mRNA O60574 O60574_HUMAN Cadherin-7 (Fragment) CDH7 317 Q53HR4 Q53HR4_HUMAN Chromosome 15 open reading frame 22 variant (Fragment) 217 Q59H35 Q59H35_HUMAN Protocadherin alpha 13 isoform 1 variant (Fragment) 921 A0A024DAS2 A0A024DAS2_HUMAN Integrin beta (Fragment) ITGB2 80 A0A024RC42 A0A024RC42_HUMAN Cadherin 2, type 1, N-cadherin (Neuronal), isoform CRA_b CDH2 hCG_22518 906 E7EMF1 E7EMF1_HUMAN Integrin alpha-2 ITGA2 815 A0A024R9D1 A0A024R9D1_HUMAN Syndecan SDC2 hCG_15745 201 Q1PBM2 Q1PBM2_HUMAN Integrin beta (Fragment) ITGB3 65 Q8NB64 Q8NB64_HUMAN cDNA FLJ34177 fis, clone FCBBF3016451, highly similar to RETINAL-CADHERIN 824 Q59EB0 Q59EB0_HUMAN Kinase insert domain receptor (A type III receptor tyrosine kinase) variant (Fragment) 1451 Q2YFE1 Q2YFE1_HUMAN Integrin beta 443 Q3B7W7 Q3B7W7_HUMAN TMED7 protein (Fragment) TMED7 134 K7EQ63 K7EQ63_HUMAN Transmembrane emp24 domain-containing protein 1 (Fragment) TMED1 191 A0A087WTR7 A0A087WTR7_HUMAN Cadherin-24 CDH24 314 K7EMU3 K7EMU3_HUMAN Integrin alpha-3 (Fragment) ITGA3 117 Q49AG2 Q49AG2_HUMAN TMED5 protein TMED5 172 A0A087WX36 A0A087WX36_HUMAN Integrin beta ITGB2 378 Q9HAX1 Q9HAX1_HUMAN Desmocollin 3 (Fragment) DSC3 316 A0A087WXI5 A0A087WXI5_HUMAN Cadherin-1 CDH1 903 M0R072 M0R072_HUMAN Transmembrane emp24 domain-containing protein 5 TMED5 120 Q8N9J3 Q8N9J3_HUMAN cDNA FLJ37047 fis, clone BRACE2012232, highly similar to Homo sapiens cadherin 20 335 (CDH20) mRNA Q8WWJ8 Q8WWJ8_HUMAN Integrin beta 378 Q59H34 Q59H34_HUMAN Protocadherin alpha 4 isoform 1 variant (Fragment) 921 A0A024DAE5 A0A024DAE5_HUMAN Integrin beta (Fragment) ITGB2 80 Q59H46 Q59H46_HUMAN Integrin beta (Fragment) 1515 Q4VAI4 Q4VAI4_HUMAN CDH5 protein CDH5 662 Q59FL1 Q59FL1_HUMAN Serine/threonine-protein kinase receptor (EC 2.7.11.30) (Fragment) 514 Q2TAL1 Q2TAL1_HUMAN CDH24 protein CDH24 314 Q59H74 Q59H74_HUMAN Integrin alpha 4 variant (Fragment) 854 A0A087WX99 A0A087WX99_HUMAN Cadherin-4 CDH4 822 Q59FN1 Q59FN1_HUMAN Integrin beta (Fragment) 166 X6R3Y6 X6R3Y6_HUMAN Cadherin-8 CDH8 745 Q59EQ1 Q59EQ1_HUMAN Cadherin 11, type 2 isoform 1 preproprotein variant (Fragment) 798 X5DQT8 X5DQT8_HUMAN Cadherin 10 type 2 isoform C (Fragment) CDH10 243 Q8N2D9 Q8N2D9_HUMAN cDNA PSEC0228 fis, clone HEMBA1006099, weakly similar to COP-COATED VESICLE 146 MEMBRANE PROTEIN P24 Q63HM4 Q63HM4_HUMAN Putative uncharacterized protein DKFZp686P18250 DKFZp686P18250 758 A0A0E3XJU3 A0A0E3XJU3_HUMAN E-cadherin 1 CDH1 882 Q68DY8 Q68DY8_HUMAN Putative uncharacterized protein DKFZp686I11137 DKFZp686I11137 667

TABLE 2 Illustrative human Type II proteins which may be incorporated into the present compositions and methods include (as used herein “Entry” refers to the human Type II protein entry in the UniProt database and “Entry name” refers to the human Type II protein entry in the UniProt database): Entry Entry name Protein names Gene names Length Q9BUJ0 ABHEA_HUMAN Protein ABHD14A (EC 3.—.—.—) (Alpha/beta hydrolase domain-containing protein 14A) ABHD14A 271 (Abhydrolase domain-containing protein 14A) UNQ1913/PRO4373 P08195 4F2_HUMAN 4F2 cell-surface antigen heavy chain (4F2hc) (4F2 heavy chain antigen) (Lymphocyte SLC3A2 MDU1 630 activation antigen 4F2 large subunit) (Solute carrier family 3 member 2) (CD antigen CD98) Q9NPC4 A4GAT_HUMAN Lactosylceramide 4-alpha-galactosyltransferase (EC 2.4.1.228) (Alpha-1,4-N- A4GALT A14GALT 353 acetylglucosaminyltransferase) (Alpha-1,4-galactosyltransferase) (Alpha4Gal-T1) (CD77 A4GALT1 synthase) (Globotriaosylceramide synthase) (Gb3 synthase) (P1/Pk synthase) (UDP- galactose: beta-D-galactosyl-beta1-R 4-alpha-D-galactosyltransferase) Q9UNA3 A4GCT_HUMAN Alpha-1,4-N-acetylglucosaminyltransferase (Alpha4GnT) (EC 2.4.1.—) A4GNT 340 Q96SE0 ABHD1_HUMAN Protein ABHD1 (EC 3.1.1.—) (Alpha/beta hydrolase domain-containing protein 1) ABHD1 LABH1 405 (Abhydrolase domain-containing protein 1) (Lung alpha/beta hydrolase 1) P08910 ABHD2_HUMAN Monoacylglycerol lipase ABHD2 (EC 3.1.1.23) (2-arachidonoylglycerol hydrolase) ABHD2 LABH2 425 (Abhydrolase domain-containing protein 2) (Lung alpha/beta hydrolase 2) (Protein PHPS1-2) Q9BV23 ABHD6_HUMAN Monoacylglycerol lipase ABHD6 (EC 3.1.1.23) (2-arachidonoylglycerol hydrolase) ABHD6 337 (Abhydrolase domain-containing protein 6) Q7L211 ABHDD_HUMAN Protein ABHD13 (EC 3.—.—.—) (Alpha/beta hydrolase domain-containing protein 13) ABHD13 C13orf6 337 (Abhydrolase domain-containing protein 13) P22760 AAAD_HUMAN Arylacetamide deacetylase (EC 3.1.1.3) AADAC DAC 399 Q5VUY2 ADCL4_HUMAN Arylacetamide deacetylase-like 4 (EC 3.1.1.—) AADACL4 407 Q8WU67 ABHD3_HUMAN Phospholipase ABHD3 (EC 3.1.1.32) (EC 3.1.1.4) (Abhydrolase domain-containing ABHD3 409 protein 3) O00468 AGRIN_HUMAN Agrin [Cleaved into: Agrin N-terminal 110 kDa subunit; Agrin C-terminal 110 kDa subunit; AGRN AGRIN 2067 Agrin C-terminal 90 kDa fragment (C90); Agrin C-terminal 22 kDa fragment (C22)] Q9Y673 ALG5_HUMAN Dolichyl-phosphate beta-glucosyltransferase (DolP-glucosyltransferase) (EC 2.4.1.117) ALG5 HSPC149 324 (Asparagine-linked glycosylation protein 5 homolog) P15144 AMPN_HUMAN Aminopeptidase N (AP-N) (hAPN) (EC 3.4.11.2) (Alanyl aminopeptidase) ANPEP APN CD13 967 (Aminopeptidase M) (AP-M) (Microsomal aminopeptidase) (Myeloid plasma membrane PEPN glycoprotein CD13) (gp150) (CD antigen CD13) Q6Q4G3 AMPQ_HUMAN Aminopeptidase Q (AP-Q) (APQ) (EC 3.4.11.—) (CHL2 antigen) (Laeverin) LVRN AQPEP 990 Q16853 AOC3_HUMAN Membrane primary amine oxidase (EC 1.4.3.21) (Copper amine oxidase) (HPAO) AOC3 VAP1 763 (Semicarbazide-sensitive amine oxidase) (SSAO) (Vascular adhesion protein 1) (VAP-1) Q9BT22 ALG1_HUMAN Chitobiosyldiphosphodolichol beta-mannosyltransferase (EC 2.4.1.142) (Asparagine- ALG1 HMAT1 HMT1 464 linked glycosylation protein 1 homolog) (Beta-1,4-mannosyltransferase) (GDP- PSEC0061 Man: GlcNAc2-PP-dolichol mannosyltransferase) (GDP-mannose-dolichol UNQ861/PRO1870 diphosphochitobiose mannosyltransferase) (Mannosyltransferase-1) (MT-1) (hMat-1) Q07075 AMPE_HUMAN Glutamyl aminopeptidase (EAP) (EC 3.4.11.7) (Aminopeptidase A) (AP-A) (Differentiation ENPEP 957 antigen gp160) (CD antigen CD249) Q9HDC9 APMAP_HUMAN Adipocyte plasma membrane-associated protein (Protein BSCv) APMAP C20orf3 416 UNQ1869/PRO4305 P07306 ASGR1_HUMAN Asialoglycoprotein receptor 1 (ASGP-R 1) (ASGPR 1) (C-type lectin domain family 4 ASGR1 CLEC4H1 291 member H1) (Hepatic lectin H1) (HL-1) Q9NR71 ASAH2_HUMAN Neutral ceramidase (N-CDase) (NCDase) (EC 3.5.1.23) (Acylsphingosine deacylase 2) ASAH2 HNAC1 780 (BCDase) (LCDase) (hCD) (N-acylsphingosine amidohydrolase 2) (Non-lysosomal ceramidase) [Cleaved into: Neutral ceramidase soluble form] Q5U4P2 ASPH1_HUMAN Aspartate beta-hydroxylase domain-containing protein 1 (EC 1.14.11.—) ASPHD1 390 Q9UN42 AT1B4_HUMAN Protein ATP1B4 (X,K-ATPase subunit beta-m) (X/potassium-transporting ATPase subunit ATP1B4 357 beta-m) Q99941 ATF6B_HUMAN Cyclic AMP-dependent transcription factor ATF-6 beta (cAMP-dependent transcription ATF6B CREBL1 703 factor ATF-6 beta) (Activating transcription factor 6 beta) (ATF6-beta) (Protein G13) G13 (cAMP response element-binding protein-related protein) (Creb-rp) (cAMP-responsive element-binding protein-like 1) [Cleaved into: Processed cyclic AMP-dependent transcription factor ATF-6 beta] Q6ICH7 ASPH2_HUMAN Aspartate beta-hydroxylase domain-containing protein 2 (EC 1.14.11.—) ASPHD2 369 P51164 ATP4B_HUMAN Potassium-transporting ATPase subunit beta (Gastric H(+)/K(+) ATPase subunit beta) ATP4B 291 (Proton pump beta chain) Q12797 ASPH_HUMAN Aspartyl/asparaginyl beta-hydroxylase (EC 1.14.11.16) (Aspartate beta-hydroxylase) ASPH BAH 758 (ASP beta-hydroxylase) (Peptide-aspartate beta-dioxygenase) P07307 ASGR2_HUMAN Asialoglycoprotein receptor 2 (ASGP-R 2) (ASGPR 2) (C-type lectin domain family 4 ASGR2 CLEC4H2 311 member H2) (Hepatic lectin H2) (HL-2) P05026 AT1B1_HUMAN Sodium/potassium-transporting ATPase subunit beta-1 (Sodium/potassium-dependent ATP1B1 ATP1B 303 ATPase subunit beta-1) P14415 AT1B2_HUMAN Sodium/potassium-transporting ATPase subunit beta-2 (Adhesion molecule in glia) ATP1B2 290 (AMOG) (Sodium/potassium-dependent ATPase subunit beta-2) P54709 AT1B3_HUMAN Sodium/potassium-transporting ATPase subunit beta-3 (Sodium/potassium-dependent ATP1B3 279 ATPase subunit beta-3) (ATPB-3) (CD antigen CD298) P18850 ATF6A_HUMAN Cyclic AMP-dependent transcription factor ATF-6 alpha (cAMP-dependent transcription ATF6 670 factor ATF-6 alpha) (Activating transcription factor 6 alpha) (ATF6-alpha) [Cleaved into: Processed cyclic AMP-dependent transcription factor ATF-6 alpha] Q9P2W7 B3GA1_HUMAN Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 (EC 2.4.1.135) B3GAT1 GLCATP 334 (Beta-1,3-glucuronyltransferase 1) (Glucuronosyltransferase P) (GlcAT-P) (UDP- GlcUA: glycoprotein beta-1,3-glucuronyltransferase) (GlcUAT-P) Q9NPZ5 B3GA2_HUMAN Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 2 (EC 2.4.1.135) B3GAT2 GLCATS 323 (Beta-1,3-glucuronyltransferase 2) (GlcAT-D) (UDP-glucuronosyltransferase S) (GlcAT-S) KIAA1963 (Glucuronosyltransferase S) O94766 B3GA3_HUMAN Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (EC 2.4.1.135) B3GAT3 335 (Beta-1,3-glucuronyltransferase 3) (Glucuronosyltransferase I) (GlcAT-I) (UDP-GlcUA: Gal beta-1,3-Gal-R glucuronyltransferase) (GlcUAT-I) Q9Y2A9 B3GN3_HUMAN N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 3 (EC 2.4.1.149) (Beta- B3GNT3 B3GALT8 372 1,3-galactosyl-O-glycosyl-glycoprotein beta-1,3-N-acetylglucosaminyltransferase) (EC TMEM3 2.4.1.146) (Beta-1,3-galactosyltransferase 8) (Beta-1,3-GalTase 8) (Beta3Gal-T8) UNQ637/PRO1266 (Beta3GalT8) (b3Gal-T8) (Beta-3-Gx-T8) (Core 1 extending beta-1,3-N- acetylglucosaminyltransferase) (Core1-beta3GlcNAcT) (Transmembrane protein 3) (UDP-Gal: beta-GlcNAc beta-1,3-galactosyltransferase 8) (UDP-GlcNAc: betaGal beta-1,3- N-acetylglucosaminyltransferase 3) (BGnT-3) (Beta-1,3-Gn-T3) (Beta-1,3-N- acetylglucosaminyltransferase 3) (Beta3Gn-T3) (UDP-galactose: beta-N- acetylglucosamine beta-1,3-galactosyltransferase 8) Q96L58 B3GT6_HUMAN Beta-1,3-galactosyltransferase 6 (Beta-1,3-GalTase 6) (Beta3Gal-T6) (Beta3GalT6) (EC B3GALT6 329 2.4.1.134) (GAG GalTII) (Galactosyltransferase II) (Galactosylxylosylprotein 3-beta- galactosyltransferase) (UDP-Gal: betaGal beta 1,3-galactosyltransferase polypeptide 6) O43505 B4GA1_HUMAN Beta-1,4-glucuronyltransferase 1 (EC 2.4.1.—) (I-beta-1,3-N- B4GAT1 B3GNT1 415 acetylglucosaminyltransferase) (iGnT) (N-acetyllactosaminide beta-1,3-N- B3GNT6 acetylglucosaminyltransferase) (Poly-N-acetyllactosamine extension enzyme) (UDP- GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 1) O75752 B3GL1_HUMAN UDP-GalNAc: beta-1,3-N-acetylgalactosaminyltransferase 1 (Beta-1,3-GalNAc-T1) (EC B3GALNT1 331 2.4.1.79) (Beta-1,3-galactosyltransferase 3) (Beta-1,3-GalTase 3) (Beta3Gal-T3) B3GALT3 (Beta3GalT3) (b3Gal-T3) (Beta-3-Gx-T3) (Galactosylgalactosylglucosylceramide beta-D- UNQ531/PRO1074 acetyl-galactosaminyltransferase) (Globoside synthase) (UDP-N- acetylgalactosamine: globotriaosylceramide beta-1,3-N-acetylgalactosaminyltransferase) Q7Z7M8 B3GN8_HUMAN UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 8 (BGnT-8) (Beta-1,3- B3GNT8 B3GALT7 397 Gn-T8) (Beta-1,3-N-acetylglucosaminyltransferase 8) (Beta3Gn-T8) (EC 2.4.1.—) BGALT15 Q9Y2C3 B3GT5_HUMAN Beta-1,3-galactosyltransferase 5 (Beta-1,3-GalTase 5) (Beta3Gal-T5) (Beta3GalT5) B3GALT5 310 (b3Gal-T5) (EC 2.4.1.—) (Beta-3-Gx-T5) (UDP-Gal: beta-GlcNAc beta-1,3- galactosyltransferase 5) (UDP-galactose: beta-N-acetylglucosamine beta-1,3- galactosyltransferase 5) Q8NFL0 B3GN7_HUMAN UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 7 (BGnT-7) (Beta-1,3- B3GNT7 401 Gn-T7) (Beta-1,3-N-acetylglucosaminyltransferase 7) (Beta3Gn-T7) (EC 2.4.1.—) O43825 B3GT2_HUMAN Beta-1,3-galactosyltransferase 2 (Beta-1,3-GalTase 2) (Beta3Gal-T2) (Beta3GalT2) (EC B3GALT2 422 2.4.1.—) (UDP-galactose: 2-acetamido-2-deoxy-D-glucose 3beta-galactosyltransferase 2) Q00973 B4GN1_HUMAN Beta-1,4 N-acetylgalactosaminyltransferase 1 (EC 2.4.1.92) ((N-acetylneuraminyl)- B4GALNT1 GALGT 533 galactosylglucosylceramide) (GM2/GD2 synthase) (GalNAc-T) SIAT2 P15291 B4GT1_HUMAN Beta-1,4-galactosyltransferase 1 (Beta-1,4-GalTase 1) (Beta4Gal-T1) (b4Gal-T1) (EC B4GALT1 GGTB2 398 2.4.1.—) (UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 1) (UDP-galactose: beta-N- acetylglucosamine beta-1,4-galactosyltransferase 1) [Cleaved into: Processed beta-1,4- galactosyltransferase 1] [Includes: Lactose synthase A protein (EC 2.4.1.22); N- acetyllactosamine synthase (EC 2.4.1.90) (Nal synthase); Beta-N- acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase (EC 2.4.1.38); Beta-N- acetylglucosaminyl-glycolipid beta-1,4-galactosyltransferase (EC 2.4.1.—)] O60513 B4GT4_HUMAN Beta-1,4-galactosyltransferase 4 (Beta-1,4-GalTase 4) (Beta4Gal-T4) (b4Gal-T4) (EC B4GALT4 344 2.4.1.—) (UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 4) (UDP-galactose: beta-N- UNQ552/PRO1109 acetylglucosamine beta-1,4-galactosyltransferase 4) [Includes: N-acetyllactosamine synthase (EC 2.4.1.90) (Nal synthase); Lactotriaosylceramide beta-1,4- galactosyltransferase (EC 2.4.1.275) (Beta-N-acetylglucosaminyl-glycolipid beta-1,4- galactosyltransferase)] O43286 B4GT5_HUMAN Beta-1,4-galactosyltransferase 5 (Beta-1,4-GalTase 5) (Beta4Gal-T5) (b4Gal-T5) (EC B4GALT5 388 2.4.1.—) (Beta-1,4-GalT II) (UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 5) (UDP-galactose: beta-N-acetylglucosamine beta-1,4-galactosyltransferase 5) Q9NY97 B3GN2_HUMAN N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 2 (EC 2.4.1.149) (Beta- B3GNT2 B3GALT7 397 1,3-N-acetylglucosaminyltransferase 1) (BGnT-1) (Beta-1,3-Gn-T1) (Beta3Gn-T1) (Beta- B3GNT1 1,3-galactosyltransferase 7) (Beta-1,3-GalTase 7) (Beta3Gal-T7) (Beta3GalT7) (b3Gal- T7) (Beta-3-Gx-T7) (UDP-Gal: beta-GlcNAc beta-1,3-galactosyltransferase 7) (UDP- GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 2) (BGnT-2) (Beta-1,3-Gn-T2) (Beta-1,3-N-acetylglucosaminyltransferase 2) (Beta3Gn-T2) (UDP-galactose: beta-N- acetylglucosamine beta-1,3-galactosyltransferase 7) O60512 B4GT3_HUMAN Beta-1,4-galactosyltransferase 3 (Beta-1,4-GalTase 3) (Beta4Gal-T3) (b4Gal-T3) (EC B4GALT3 393 2.4.1.—) (UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 3) (UDP-galactose: beta-N- acetylglucosamine beta-1,4-galactosyltransferase 3) [Includes: N-acetyllactosamine synthase (EC 2.4.1.90) (Nal synthase); Beta-N-acetylglucosaminylglycopeptide beta-1,4- galactosyltransferase (EC 2.4.1.38); Beta-N-acetylglucosaminyl-glycolipid beta-1,4- galactosyltransferase (EC 2.4.1.—)] Q9Y5Z6 B3GT1_HUMAN Beta-1,3-galactosyltransferase 1 (Beta-1,3-GalTase 1) (Beta3Gal-T1) (Beta3GalT1) (EC B3GALT1 326 2.4.1.—) (UDP-galactose: beta-N-acetyl-glucosamine-beta-1,3-galactosyltransferase 1) O96024 B3GT4_HUMAN Beta-1,3-galactosyltransferase 4 (Beta-1,3-GalTase 4) (Beta3Gal-T4) (Beta3GalT4) B3GALT4 GALT4 378 (GalT4) (b3Gal-T4) (EC 2.4.1.62) (Gal-T2) (Ganglioside galactosyltransferase) (UDP- galactose: beta-N-acetyl-galactosamine-beta-1,3-galactosyltransferase) Q76KP1 B4GN4_HUMAN N-acetyl-beta-glucosaminyl-glycoprotein 4-beta-N-acetylgalactosaminyltransferase 1 B4GALNT4 1039 (NGalNAc-T1) (EC 2.4.1.244) (Beta-1,4-N-acetylgalactosaminyltransferase IV) (Beta4GalNAc-T4) (Beta4GalNAcT4) O60909 B4GT2_HUMAN Beta-1,4-galactosyltransferase 2 (Beta-1,4-GalTase 2) (Beta4Gal-T2) (b4Gal-T2) (EC B4GALT2 372 2.4.1.—) (UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 2) (UDP-galactose: beta-N- acetylglucosamine beta-1,4-galactosyltransferase 2) [Includes: Lactose synthase A protein (EC 2.4.1.22); N-acetyllactosamine synthase (EC 2.4.1.90) (Nal synthase); Beta- N-acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase (EC 2.4.1.38); Beta-N- acetylglucosaminyl-glycolipid beta-1,4-galactosyltransferase (EC 2.4.1.—)] Q9UBX8 B4GT6_HUMAN Beta-1,4-galactosyltransferase 6 (Beta-1,4-GalTase 6) (Beta4Gal-T6) (b4Gal-T6) (UDP- B4GALT6 382 Gal: beta-GlcNAc beta-1,4-galactosyltransferase 6) (UDP-galactose: beta-N- acetylglucosamine beta-1,4-galactosyltransferase 6) [Includes: Glucosylceramide beta- 1,4-galactosyltransferase (EC 2.4.1.274) (Lactosylceramide synthase) (LacCer synthase) (UDP-Gal: glucosylceramide beta-1,4-galactosyltransferase)] Q9UBV7 B4GT7_HUMAN Beta-1,4-galactosyltransferase 7 (Beta-1,4-GalTase 7) (Beta4Gal-T7) (b4Gal-T7) (EC B4GALT7 XGALT1 327 2.4.1.—) (UDP-Gal: beta-GlcNAc beta-1,4-galactosyltransferase 7) (UDP-galactose: beta-N- UNQ748/PRO1478 acetylglucosamine beta-1,4-galactosyltransferase 7) [Includes: Xylosylprotein 4-beta- galactosyltransferase (EC 2.4.1.133) (Proteoglycan UDP-galactose: beta-xylose beta1,4- galactosyltransferase I) (UDP-galactose: beta-xylose beta-1,4-galactosyltransferase) (XGPT) (XGalT-1) (Xylosylprotein beta-1,4-galactosyltransferase)] Q8NCR0 B3GL2_HUMAN UDP-GalNAc: beta-1,3-N-acetylgalactosaminyltransferase 2 (Beta-1,3-GalNAc-T2) (EC B3GALNT2 500 2.4.1.—) (Beta-1,3-N-acetylgalactosaminyltransferase II) Q9C0J1 B3GN4_HUMAN N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 4 (EC 2.4.1.149) (UDP- B3GNT4 378 GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 4) (BGnT-4) (Beta-1,3-Gn-T4) UNQ1898/PRO4344 (Beta-1,3-N-acetylglucosaminyltransferase 4) (Beta3Gn-T4) Q6ZMB0 B3GN6_HUMAN Acetylgalactosaminyl-O-glycosyl-glycoprotein beta-1,3-N-acetylglucosaminyltransferase B3GNT6 384 (EC 2.4.1.147) (Core 3 synthase) (UDP-GlcNAc: betaGal beta-1,3-N- acetylglucosaminyltransferase 6) (BGnT-6) (Beta-1,3-Gn-T6) (Beta-1,3-N- acetylglucosaminyltransferase 6) (Beta3Gn-T6) Q9BYG0 B3GN5_HUMAN Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (EC 2.4.1.206) B3GNT5 378 (Lactotriaosylceramide synthase) (Lc(3)Cer synthase) (Lc3 synthase) (UDP-GlcNAc: beta- Gal beta-1,3-N-acetylglucosaminyltransferase 5) (BGnT-5) (Beta-1,3-Gn-T5) (Beta-1,3-N- acetylglucosaminyltransferase 5) (Beta3Gn-T5) Q6UX72 B3GN9_HUMAN UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 9 (BGnT-9) (Beta-1,3- B3GNT9 402 Gn-T9) (Beta-1,3-N-acetylglucosaminyltransferase 9) (Beta3Gn-T9) (EC 2.4.1.—) UNQ1922/PRO4397 Q6L9W6 B4GN3_HUMAN Beta-1,4-N-acetylgalactosaminyltransferase 3 (B4GalNAcT3) (Beta4GalNAc-T3) B4GALNT3 998 (Beta4GalNAcT3) (EC 2.4.1.244) (Beta-1,4-N-acetylgalactosaminyltransferase III) (N- acetyl-beta-glucosaminyl-glycoprotein 4-beta-N-acetylgalactosaminyltransferase 2) (NGalNAc-T2) Q6Y288 B3GLT_HUMAN Beta-1,3-glucosyltransferase (Beta3Glc-T) (EC 2.4.1.—) (Beta 3-glucosyltransferase) B3GLCT B3GALTL 498 (Beta-3-glycosyltransferase-like) B3GTL Q8NHY0 B4GN2_HUMAN Beta-1,4 N-acetylgalactosaminyltransferase 2 (EC 2.4.1.—) (Sd(a) beta-1,4-GalNAc B4GALNT2 566 transferase) (UDP-GalNAc: Neu5Aca2-3Galb-R b1,4-N-acetylgalactosaminyltransferase) GALGT2 P0DN25 C1C1L_HUMAN C1GALT1-specific chaperone 1-like protein C1GALT1C1L 315 P16442 BGAT_HUMAN Histo-blood group ABO system transferase (Fucosylglycoprotein 3-alpha- ABO 354 galactosyltransferase) (Fucosylglycoprotein alpha-N-acetylgalactosaminyltransferase) (Glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase) (EC 2.4.1.40) (Glycoprotein-fucosylgalactoside alpha-galactosyltransferase) (EC 2.4.1.37) (Histo-blood group A transferase) (A transferase) (Histo-blood group B transferase) (B transferase) (NAGAT) [Cleaved into: Fucosylglycoprotein alpha-N-acetylgalactosaminyltransferase soluble form] Q9NS00 C1GLT_HUMAN Glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (EC 2.4.1.122) C1GALT1 363 (B3Gal-T8) (Core 1 O-glycan T-synthase) (Core 1 UDP-galactose: N- acetylgalactosamine-alpha-R beta 1,3-galactosyltransferase 1) (Beta-1,3- galactosyltransferase) (Core 1 beta1,3-galactosyltransferase 1) (C1GalT1) (Core 1 beta3- Gal-T1) Q10589 BST2_HUMAN Bone marrow stromal antigen 2 (BST-2) (HM1.24 antigen) (Tetherin) (CD antigen CD317) BST2 180 Q96EU7 C1GLC_HUMAN C1GALT1-specific chaperone 1 (C38H2-like protein 1) (C38H2-L1) (Core 1 beta1,3- C1GALT1C1 318 galactosyltransferase 2) (C1Gal-T2) (C1GalT2) (Core 1 beta3-Gal-T2) (Core 1 beta3- COSMC HSPC067 galactosyltransferase-specific molecular chaperone) MSTP143 UNQ273/PRO310 Q9UIR0 BTNL2_HUMAN Butyrophilin-like protein 2 (BTL-II) BTNL2 455 Q6P4E1 CASC4_HUMAN Protein CASC4 (Cancer susceptibility candidate gene 4 protein) CASC4 433 UNQ2573/PRO6308 Q9NNX6 CD209_HUMAN CD209 antigen (C-type lectin domain family 4 member L) (Dendritic cell-specific ICAM-3- CD209 CLEC4L 404 grabbing non-integrin 1) (DC-SIGN) (DC-SIGN1) (CD antigen CD209) Q8WVQ1 CANT1_HUMAN Soluble calcium-activated nucleotidase 1 (SCAN-1) (EC 3.6.1.6) (Apyrase homolog) CANT1 SHAPY 401 (Putative MAPK-activating protein PM09) (Putative NF-kappa-B-activating protein 107) P29965 CD40L_HUMAN CD40 ligand (CD40-L) (T-cell antigen Gp39) (TNF-related activation protein) (TRAP) CD40LG CD40L 261 (Tumor necrosis factor ligand superfamily member 5) (CD antigen CD154) [Cleaved into: TNFSF5 TRAP CD40 ligand, membrane form; CD40 ligand, soluble form] P21854 CD72_HUMAN B-cell differentiation antigen CD72 (Lyb-2) (CD antigen CD72) CD72 359 Q07108 CD69_HUMAN Early activation antigen CD69 (Activation inducer molecule) (AIM) (BL-AC/P26) (C-type CD69 CLEC2C 199 lectin domain family 2 member C) (EA1) (Early T-cell activation antigen p60) (GP32/28) (Leukocyte surface antigen Leu-23) (MLR-3) (CD antigen CD69) Q9ULG6 CCPG1_HUMAN Cell cycle progression protein 1 (Cell cycle progression restoration protein 8) CCPG1 CCP8 757 CPR8 KIAA1254 Q8TDX6 CGAT1_HUMAN Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CsGalNAcT-1) (EC 2.4.1.174) CSGALNACT1 532 (Chondroitin beta-1,4-N-acetylgalactosaminyltransferase 1) (Beta4GalNAcT-1) CHGN GALNACT1 UNQ656/PRO1287 P32970 CD70_HUMAN CD70 antigen (CD27 ligand) (CD27-L) (Tumor necrosis factor ligand superfamily member CD70 CD27L 193 7) (CD antigen CD70) CD27LG TNFSF7 Q8IZ52 CHSS2_HUMAN Chondroitin sulfate synthase 2 (EC 2.4.1.175) (EC 2.4.1.226) (Chondroitin CHPF CSS2 775 glucuronyltransferase 2) (Chondroitin-polymerizing factor) (ChPF) (Glucuronosyl-N- UNQ651/PRO1281 acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase II) (N- acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase II) (N- acetylgalactosaminyltransferase 2) Q9GZX3 CHST6_HUMAN Carbohydrate sulfotransferase 6 (EC 2.8.2.—) (Corneal N-acetylglucosamine-6-O- CHST6 395 sulfotransferase) (C-GlcNAc6ST) (hCGn6ST) (Galactose/N-acetylglucosamine/N- acetylglucosamine 6-O-sulfotransferase 4-beta) (GST4-beta) (N-acetylglucosamine 6-O- sulfotransferase 5) (GlcNAc6ST-5) (Gn6st-5) Q9NRB3 CHSTC_HUMAN Carbohydrate sulfotransferase 12 (EC 2.8.2.5) (Chondroitin 4-O-sulfotransferase 2) CHST12 414 (Chondroitin 4-sulfotransferase 2) (C4ST-2) (C4ST2) (Sulfotransferase Hlo) UNQ500/PRO1017 P28907 CD38_HUMAN ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (EC 3.2.2.6) (2′-phospho-ADP-ribosyl CD38 300 cyclase) (2′-phospho-ADP-ribosyl cyclase/2′-phospho-cyclic-ADP-ribose transferase) (EC 2.4.99.20) (2′-phospho-cyclic-ADP-ribose transferase) (ADP-ribosyl cyclase 1) (ADPRC 1) (Cyclic ADP-ribose hydrolase 1) (cADPr hydrolase 1) (T10) (CD antigen CD38) Q8N6G5 CGAT2_HUMAN Chondroitin sulfate N-acetylgalactosaminyltransferase 2 (EC 2.4.1.174) (Chondroitin CSGALNACT2 542 beta-1,4-N-acetylgalactosaminyltransferase 2) (Beta4GalNAcT-2) (GalNAcT-2) CHGN2 GALNACT2 PRO0082 Q5QGZ9 CL12A_HUMAN C-type lectin domain family 12 member A (C-type lectin-like molecule 1) (CLL-1) CLEC12A CLL1 265 (Dendritic cell-associated lectin 2) (DCAL-2) (Myeloid inhibitory C-type lectin-like DCAL2 MICL receptor) (MICL) Q9P2E5 CHPF2_HUMAN Chondroitin sulfate glucuronyltransferase (EC 2.4.1.226) (CSGlcA-T) (Chondroitin CHPF2 CHSY3 772 glucuronyltransferase) (Chondroitin polymerizing factor 2) (ChPF-2) (Chondroitin CSGLCAT synthase 3) (ChSy-3) (N-acetylgalactosaminyl-proteoglycan 3-beta- KIAA1402 glucuronosyltransferase) UNQ299/PRO339 Q70JA7 CHSS3_HUMAN Chondroitin sulfate synthase 3 (EC 2.4.1.175) (EC 2.4.1.226) (Carbohydrate synthase 2) CHSY3 CHSY2 882 (Chondroitin glucuronyltransferase 3) (Chondroitin synthase 2) (ChSy-2) (Glucuronosyl- CSS3 N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase II) (N- acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase 3) (N- acetylgalactosaminyltransferase 3) Q9Y4C5 CHST2_HUMAN Carbohydrate sulfotransferase 2 (EC 2.8.2.—) (Galactose/N-acetylglucosamine/N- CHST2 GN6ST 530 acetylglucosamine 6-O-sulfotransferase 2) (GST-2) (N-acetylglucosamine 6-O- sulfotransferase 1) (GlcNAc6ST-1) (Gn6ST-1) Q8NCG5 CHST4_HUMAN Carbohydrate sulfotransferase 4 (EC 2.8.2.—) (Galactose/N-acetylglucosamine/N- CHST4 386 acetylglucosamine 6-O-sulfotransferase 3) (GST-3) (High endothelial cells N- acetylglucosamine 6-O-sulfotransferase) (HEC-GlcNAc6ST) (L-selectin ligand sulfotransferase) (LSST) (N-acetylglucosamine 6-O-sulfotransferase 2) (GlcNAc6ST-2) (Gn6st-2) O43529 CHSTA_HUMAN Carbohydrate sulfotransferase 10 (EC 2.8.2.—) (HNK-1 sulfotransferase) (HNK-1ST) CHST10 356 (HNK1ST) (HuHNK-1ST) Q92478 CLC2B_HUMAN C-type lectin domain family 2 member B (Activation-induced C-type lectin) (C-type lectin CLEC2B AICL 149 superfamily member 2) (IFN-alpha-2b-inducing-related protein 1) CLECSF2 IFNRG1 Q6UXN8 CLC9A_HUMAN C-type lectin domain family 9 member A CLEC9A 241 UNQ9341/PRO34046 Q6UWU4 CF089_HUMAN Bombesin receptor-activated protein C6orf89 (Amfion) C6orf89 BRAP 347 UNQ177/PRO203 Q86X52 CHSS1_HUMAN Chondroitin sulfate synthase 1 (EC 2.4.1.175) (EC 2.4.1.226) (Chondroitin CHSY1 CHSY CSS1 802 glucuronyltransferase 1) (Chondroitin synthase 1) (ChSy-1) (Glucuronosyl-N- KIAA0990 acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase 1) (N- UNQ756/PRO1487 acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase 1) (N- acetylgalactosaminyltransferase 1) Q8NET6 CHSTD_HUMAN Carbohydrate sulfotransferase 13 (EC 2.8.2.5) (Chondroitin 4-O-sulfotransferase 3) CHST13 341 (Chondroitin 4-sulfotransferase 3) (C4ST-3) (C4ST3) Q7LFX5 CHSTF_HUMAN Carbohydrate sulfotransferase 15 (EC 2.8.2.33) (B-cell RAG-associated gene protein) CHST15 BRAG 561 (hBRAG) (N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase) (GalNAc4S-6ST) GALNAC4S6ST KIAA0598 Q9P126 CLC1B_HUMAN C-type lectin domain family 1 member B (C-type lectin-like receptor 2) (CLEC-2) CLEC1B CLEC2 229 UNQ721/PRO1384 Q8IZS7 CLCL1_HUMAN C-type lectin-like domain family 1 (Dendritic cell-associated lectin 1) (DC-associated CLECL1 DCAL1 167 lectin-1) (DCAL-1) O43916 CHST1_HUMAN Carbohydrate sulfotransferase 1 (EC 2.8.2.21) (Galactose/N-acetylglucosamine/N- CHST1 411 acetylglucosamine 6-O-sulfotransferase 1) (GST-1) (Keratan sulfate Gal-6 sulfotransferase) (KS6ST) (KSGal6ST) (KSST) Q7LGC8 CHST3_HUMAN Carbohydrate sulfotransferase 3 (EC 2.8.2.17) (Chondroitin 6-O-sulfotransferase 1) CHST3 479 (C6ST-1) (Chondroitin 6-sulfotransferase) (Galactose/N-acetylglucosamine/N- acetylglucosamine 6-O-sulfotransferase 0) (GST-0) Q9GZS9 CHST5_HUMAN Carbohydrate sulfotransferase 5 (EC 2.8.2.—) (Galactose/N-acetylglucosamine/N- CHST5 411 acetylglucosamine 6-O-sulfotransferase 4-alpha) (GST4-alpha) (Intestinal N- acetylglucosamine-6-O-sulfotransferase) (I-GlcNAc6ST) (Intestinal GlcNAc-6- sulfotransferase) (hIGn6ST) (N-acetylglucosamine 6-O-sulfotransferase 3) (GlcNAc6ST- 3) (Gn6st-3) Q9NPF2 CHSTB_HUMAN Carbohydrate sulfotransferase 11 (EC 2.8.2.5) (Chondroitin 4-O-sulfotransferase 1) CHST11 352 (Chondroitin 4-sulfotransferase 1) (C4S-1) (C4ST-1) (C4ST1) Q9UMR7 CLC4A_HUMAN C-type lectin domain family 4 member A (C-type lectin DDB27) (C-type lectin superfamily CLEC4A CLECSF6 237 member 6) (Dendritic cell immunoreceptor) (Lectin-like immunoreceptor) DCIR LLIR HDCGC13P Q8WXI8 CLC4D_HUMAN C-type lectin domain family 4 member D (C-type lectin superfamily member 8) (C-type CLEC4D CLECSF8 215 lectin-like receptor 6) (CLEC-6) MCL Q8N1N0 CLC4F_HUMAN C-type lectin domain family 4 member F (C-type lectin superfamily member 13) (C-type CLEC4F CLECSF13 589 lectin 13) Q6UXB4 CLC4G_HUMAN C-type lectin domain family 4 member G (Liver and lymph node sinusoidal endothelial cell CLEC4G 293 C-type lectin) (LSECtin) UNQ431/PR0792 Q9BXN2 CLC7A_HUMAN C-type lectin domain family 7 member A (Beta-glucan receptor) (C-type lectin superfamily CLEC7A BGR 247 member 12) (Dendritic cell-associated C-type lectin 1) (DC-associated C-type lectin 1) CLECSF12 (Dectin-1) DECTIN1 UNQ539/PRO1082 Q86VU5 CMTD1_HUMAN Catechol O-methyltransferase domain-containing protein 1 (EC 2.1.1.—) COMTD1 262 UNQ766/PRO1558 Q9NS84 CHST7_HUMAN Carbohydrate sulfotransferase 7 (EC 2.8.2.—) (EC 2.8.2.17) (Chondroitin 6- CHST7 486 sulfotransferase 2) (C6ST-2) (Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O- sulfotransferase 5) (GST-5) (N-acetylglucosamine 6-O-sulfotransferase 4) (GlcNAc6ST-4) (Gn6st-4) Q8NCH0 CHSTE_HUMAN Carbohydrate sulfotransferase 14 (EC 2.8.2.35) (Dermatan 4-sulfotransferase 1) (D4ST- CHST14 D4ST1 376 1) (hD4ST1) UNQ1925/PRO4400 Q6UVW9 CLC2A_HUMAN C-type lectin domain family 2 member A (Keratinocyte-associated C-type lectin) (KACL) CLEC2A KACL 174 (Proliferation-induced lymphocyte-associated receptor) (PILAR) UNQ5792/PRO19597 Q8WTT0 CLC4C_HUMAN C-type lectin domain family 4 member C (Blood dendritic cell antigen 2) (BDCA-2) (C-type CLEC4C BDCA2 213 lectin superfamily member 7) (Dendritic lectin) (CD antigen CD303) CLECSF11 CLECSF7 DLEC HECL UNQ9361/PRO34150 Q9ULY5 CLC4E_HUMAN C-type lectin domain family 4 member E (C-type lectin superfamily member 9) CLEC4E CLECSF9 219 (Macrophage-inducible C-type lectin) MINCLE UNQ218/PRO244 Q9H2A9 CHST8_HUMAN Carbohydrate sulfotransferase 8 (EC 2.8.2.—) (GalNAc-4-O-sulfotransferase 1) (GalNAc-4- CHST8 424 ST1) (GalNAc4ST-1) (N-acetylgalactosamine-4-O-sulfotransferase 1) Q8IUN9 CLC10_HUMAN C-type lectin domain family 10 member A (C-type lectin superfamily member 14) CLEC10A 316 (Macrophage lectin 2) (CD antigen CD301) CLECSF13 CLECSF14 HML Q8NC01 CLC1A_HUMAN C-type lectin domain family 1 member A (C-type lectin-like receptor 1) (CLEC-1) CLEC1A CLEC1 280 UNQ569/PRO1131 Q9UJ71 CLC4K_HUMAN C-type lectin domain family 4 member K (Langerin) (CD antigen CD207) CD207 CLEC4K 328 Q7L1S5 CHST9_HUMAN Carbohydrate sulfotransferase 9 (EC 2.8.2.—) (GalNAc-4-O-sulfotransferase 2) (GalNAc-4- CHST9 443 ST2) (GalNAc4ST-2) (N-acetylgalactosamine-4-O-sulfotransferase 2) UNQ2549/PRO6175 Q07065 CKAP4_HUMAN Cytoskeleton-associated protein 4 (63-kDa cytoskeleton-linking membrane protein) CKAP4 602 (Climp-63) (p63) Q2HXU8 CL12B_HUMAN C-type lectin domain family 12 member B (Macrophage antigen H) CLEC12B 276 UNQ5782/PRO16089 Q6ZS10 CL17A_HUMAN C-type lectin domain family 17, member A (Prolectin) CLEC17A 378 Q9NY25 CLC5A_HUMAN C-type lectin domain family 5 member A (C-type lectin superfamily member 5) (Myeloid CLEC5A CLECSF5 188 DAP12-associating lectin 1) (MDL-1) MDL1 Q6EIG7 CLC6A_HUMAN C-type lectin domain family 6 member A (C-type lectin superfamily member 10) (Dendritic CLEC6A CLECSF10 209 cell-associated C-type lectin 2) (DC-associated C-type lectin 2) (Dectin-2) DECTIN2 P21964 COMT_HUMAN Catechol O-methyltransferase (EC 2.1.1.6) COMT 271 Q9UHP7 CLC2D_HUMAN C-type lectin domain family 2 member D (Lectin-like NK cell receptor) (Lectin-like CLEC2D CLAX 191 transcript 1) (LLT-1) (Osteoclast inhibitory lectin) LLT1 OCIL Q9H2X3 CLC4M_HUMAN C-type lectin domain family 4 member M (CD209 antigen-like protein 1) (DC-SIGN- CLEC4M CD209L 399 related protein) (DC-SIGNR) (Dendritic cell-specific ICAM-3-grabbing non-integrin 2) (DC- CD209L1 CD299 SIGN2) (Liver/lymph node-specific ICAM-3-grabbing non-integrin) (L-SIGN) (CD antigen CD299) Q5KU26 COL12_HUMAN Collectin-12 (Collectin placenta protein 1) (CL-P1) (hCL-P1) (Nurse cell scavenger COLEC12 CLP1 742 receptor 2) (Scavenger receptor class A member 4) (Scavenger receptor with C-type NSR2 SCARA4 lectin) SRCL Q5TAT6 CODA1_HUMAN Collagen alpha-1(XIII) chain (COLXIIIA1) COL13A1 717 Q96BA8 CR3L1_HUMAN Cyclic AMP-responsive element-binding protein 3-like protein 1 (cAMP-responsive CREB3L1 OASIS 519 element-binding protein 3-like protein 1) (Old astrocyte specifically-induced substance) PSEC0238 (OASIS) [Cleaved into: Processed cyclic AMP-responsive element-binding protein 3-like protein 1] Q86Y22 CONA1_HUMAN Collagen alpha-1(XXIII) chain COL23A1 540 Q70SY1 CR3L2_HUMAN Cyclic AMP-responsive element-binding protein 3-like protein 2 (cAMP-responsive CREB3L2 BBF2H7 520 element-binding protein 3-like protein 2) (BBF2 human homolog on chromosome 7) [Cleaved into: Processed cyclic AMP-responsive element-binding protein 3-like protein 2] Q9UMD9 COHA1_HUMAN Collagen alpha-1(XVII) chain (180 kDa bullous pemphigoid antigen 2) (Bullous COL17A1 BP180 1497 pemphigoid antigen 2) [Cleaved into: 120 kDa linear IgA disease antigen (120 kDa linear BPAG2 IgA dermatosis antigen) (Linear IgA disease antigen 1) (LAD-1); 97 kDa linear IgA disease antigen (97 kDa linear IgA bullous dermatosis antigen) (97 kDa LAD antigen) (97-LAD) (Linear IgA bullous disease antigen of 97 kDa) (LABD97)] Q8N1L4 CP4Z2_HUMAN Putative inactive cytochrome P450 family member 4Z2 CYP4Z2P 340 Q9BXS0 COPA1_HUMAN Collagen alpha-1(XXV) chain (Alzheimer disease amyloid-associated protein) (AMY) COL25A1 654 (CLAC-P) [Cleaved into: Collagen-like Alzheimer amyloid plaque component (CLAC)] Q9Y5Q5 CORIN_HUMAN Atrial natriuretic peptide-converting enzyme (EC 3.4.21.—) (Corin) (Heart-specific serine CORIN CRN 1042 proteinase ATC2) (Pro-ANP-converting enzyme) (Transmembrane protease serine 10) TMPRSS10 [Cleaved into: Atrial natriuretic peptide-converting enzyme, N-terminal propeptide; Atrial natriuretic peptide-converting enzyme, activated protease fragment; Atrial natriuretic peptide-converting enzyme, 180 kDa soluble fragment; Atrial natriuretic peptide- converting enzyme, 160 kDa soluble fragment; Atrial natriuretic peptide-converting enzyme, 100 kDa soluble fragment] Q86W10 CP4Z1_HUMAN Cytochrome P4504Z1 (EC 1.14.14.1) (CYPIVZ1) CYP4Z1 505 UNQ3060/PRO9882 O43889 CREB3_HUMAN Cyclic AMP-responsive element-binding protein 3 (CREB-3) (cAMP-responsive element- CREB3 LZIP 395 binding protein 3) (Leucine zipper protein) (Luman) (Transcription factor LZIP-alpha) [Cleaved into: Processed cyclic AMP-responsive element-binding protein 3 (N-terminal Luman) (Transcriptionally active form)] Q8TEY5 CR3L4_HUMAN Cyclic AMP-responsive element-binding protein 3-like protein 4 (cAMP-responsive CREB3L4 AIBZIP 395 element-binding protein 3-like protein 4) (Androgen-induced basic leucine zipper protein) CREB4 JAL (AlbZIP) (Attaching to CRE-like 1) (ATCE1) (Cyclic AMP-responsive element-binding protein 4) (CREB-4) (cAMP-responsive element-binding protein 4) (Transcript induced in spermiogenesis protein 40) (Tisp40) (hJAL) [Cleaved into: Processed cyclic AMP- responsive element-binding protein 3-like protein 4] Q68CJ9 CR3L3_HUMAN Cyclic AMP-responsive element-binding protein 3-like protein 3 (cAMP-responsive CREB3L3 CREBH 461 element-binding protein 3-like protein 3) (Transcription factor CREB-H) [Cleaved into: HYST1481 Processed cyclic AMP-responsive element-binding protein 3-like protein 3] P37059 DHB2_HUMAN Estradiol 17-beta-dehydrogenase 2 (EC 1.1.1.62) (17-beta-hydroxysteroid HSD17B2 EDH17B2 387 dehydrogenase type 2) (17-beta-HSD 2) (20 alpha-hydroxysteroid dehydrogenase) (20- SDR9C2 alpha-HSD) (E2DH) (Microsomal 17-beta-hydroxysteroid dehydrogenase) (Short chain dehydrogenase/reductase family 9C member 2) (Testosterone 17-beta-dehydrogenase) (EC 1.1.1.239) P27487 DPP4_HUMAN Dipeptidyl peptidase 4 (EC 3.4.14.5) (ADABP) (Adenosine deaminase complexing protein DPP4 ADCP2 CD26 766 2) (ADCP-2) (Dipeptidyl peptidase IV) (DPP IV) (T-cell activation antigen CD26) (TP103) (CD antigen CD26) [Cleaved into: Dipeptidyl peptidase 4 membrane form (Dipeptidyl peptidase IV membrane form); Dipeptidyl peptidase 4 soluble form (Dipeptidyl peptidase IV soluble form)] P28845 DHI1_HUMAN Corticosteroid 11-beta-dehydrogenase isozyme 1 (EC 1.1.1.146) (11-beta-hydroxysteroid HSD11B1 HSD11 292 dehydrogenase 1) (11-DH) (11-beta-HSD1) (Short chain dehydrogenase/reductase family HSD11L SDR26C1 26C member 1) P09172 DOPO_HUMAN Dopamine beta-hydroxylase (EC 1.14.17.1) (Dopamine beta-monooxygenase) [Cleaved DBH 617 into: Soluble dopamine beta-hydroxylase] Q8N608 DPP10_HUMAN Inactive dipeptidyl peptidase 10 (Dipeptidyl peptidase IV-related protein 3) (DPRP-3) DPP10 DPRP3 796 (Dipeptidyl peptidase X) (DPP X) (Dipeptidyl peptidase-like protein 2) (DPL2) KIAA1492 P42658 DPP6_HUMAN Dipeptidyl aminopeptidase-like protein 6 (DPPX) (Dipeptidyl aminopeptidase-related DPP6 865 protein) (Dipeptidyl peptidase 6) (Dipeptidyl peptidase IV-like protein) (Dipeptidyl peptidase VI) (DPP VI) Q6IAN0 DRS7B_HUMAN Dehydrogenase/reductase SDR family member 7B (EC 1.1.—.—) (Short-chain DHRS7B SDR32C1 325 dehydrogenase/reductase family 32C member 1) CGI-93 UNQ212/PRO238 O60344 ECE2_HUMAN Endothelin-converting enzyme 2 (ECE-2) [Includes: Methyltransferase-like region (EC ECE2 KIAA0604 883 2.1.1.—); Endothelin-converting enzyme 2 region (EC 3.4.24.71)] UNQ403/PRO740 O75923 DYSF_HUMAN Dysferlin (Dystrophy-associated fer-1-like protein) (Fer-1-like protein 1) DYSF FER1L1 2080 O95672 ECEL1_HUMAN Endothelin-converting enzyme-like 1 (EC 3.4.24.—) (Xce protein) ECEL1 XCE 775 UNQ2431/PRO4991 Q92838 EDA_HUMAN Ectodysplasin-A (Ectodermal dysplasia protein) (EDA protein) [Cleaved into: EDA ED1 EDA2 391 Ectodysplasin-A, membrane form; Ectodysplasin-A, secreted form] P42892 ECE1_HUMAN Endothelin-converting enzyme 1 (ECE-1) (EC 3.4.24.71) ECE1 770 Q92611 EDEM1_HUMAN ER degradation-enhancing alpha-mannosidase-like protein 1 EDEM1 EDEM 657 KIAA0212 O75354 ENTP6_HUMAN Ectonucleoside triphosphate diphosphohydrolase 6 (NTPDase 6) (EC 3.6.1.6) (CD39 ENTPD6 CD39L2 484 antigen-like 2) IL6ST2 P98073 ENTK_HUMAN Enteropeptidase (EC 3.4.21.9) (Enterokinase) (Serine protease 7) (Transmembrane TMPRSS15 ENTK 1019 protease serine 15) [Cleaved into: Enteropeptidase non-catalytic heavy chain; PRSS7 Enteropeptidase catalytic light chain] P22413 ENPP1_HUMAN Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (E-NPP 1) ENPP1 M6S1 NPPS 925 (Membrane component chromosome 6 surface marker 1) (Phosphodiesterase PC1 PDNP1 I/nucleotide pyrophosphatase 1) (Plasma-cell membrane glycoprotein PC-1) [Includes: Alkaline phosphodiesterase I (EC 3.1.4.1); Nucleotide pyrophosphatase (NPPase) (EC 3.6.1.9)] O14638 ENPP3_HUMAN Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (E-NPP 3) ENPP3 PDNP3 875 (Phosphodiesterase I beta) (PD-Ibeta) (Phosphodiesterase I/nucleotide pyrophosphatase 3) (CD antigen CD203c) [Includes: Alkaline phosphodiesterase I (EC 3.1.4.1); Nucleotide pyrophosphatase (NPPase) (EC 3.6.1.9)] O43909 EXTL3_HUMAN Exostosin-like 3 (EC 2.4.1.223) (EXT-related protein 1) (Glucuronyl-galactosyl- EXTL3 EXTL1L 919 proteoglycan 4-alpha-N-acetylglucosaminyltransferase) (Hereditary multiple exostoses EXTR1 KIAA0519 gene isolog) (Multiple exostosis-like protein 3) (Putative tumor suppressor protein EXTL3) Q6UWH4 F198B_HUMAN Protein FAM198B (Expressed in nerve and epithelium during development) FAM198B C4orf18 519 ENED AD021 UNQ2512/PRO6001 Q9H0X4 F234A_HUMAN Protein FAM234A (Protein ITFG3) FAM234A C16orf9 552 ITFG3 Q5VUD6 FA69B_HUMAN Protein FAM69B FAM69B C9orf136 431 PP6977 Q8IUS5 EPHX4_HUMAN Epoxide hydrolase 4 (EC 3.3.—.—) (Abhydrolase domain-containing protein 7) (Epoxide EPHX4 ABHD7 362 hydrolase-related protein) EPHXRP O94905 ERLN2_HUMAN Erlin-2 (Endoplasmic reticulum lipid raft-associated protein 2) (Stomatin-prohibitin-flotillin- ERLIN2 C8orf2 339 HflC/K domain-containing protein 2) (SPFH domain-containing protein 2) SPFH2 UNQ2441/PRO5003/ PRO9924 Q93063 EXT2_HUMAN Exostosin-2 (EC 2.4.1.224) (EC 2.4.1.225) (Glucuronosyl-N-acetylglucosaminyl- EXT2 718 proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N- acetylglucosaminyltransferase) (Multiple exostoses protein 2) (Putative tumor suppressor protein EXT2) Q9NZ08 ERAP1_HUMAN Endoplasmic reticulum aminopeptidase 1 (EC 3.4.11.—) (ARTS-1) (Adipocyte-derived ERAP1 APPILS 941 leucine aminopeptidase) (A-LAP) (Aminopeptidase PILS) (Puromycin-insensitive leucyl- ARTS1 KIAA0525 specific aminopeptidase) (PILS-AP) (Type 1 tumor necrosis factor receptor shedding UNQ584/PRO1154 aminopeptidase regulator) Q6P179 ERAP2_HUMAN Endoplasmic reticulum aminopeptidase 2 (EC 3.4.11.—) (Leukocyte-derived arginine ERAP2 LRAP 960 aminopeptidase) (L-RAP) O75477 ERLN1_HUMAN Erlin-1 (Endoplasmic reticulum lipid raft-associated protein 1) (Protein KE04) (Stomatin- ERLIN1 C10orf69 346 prohibitin-flotillin-HflC/K domain-containing protein 1) (SPFH domain-containing protein 1) KE04 KEO4 SPFH1 Q92935 EXTL1_HUMAN Exostosin-like 1 (EC 2.4.1.224) (Exostosin-L) (Glucuronosyl-N-acetylglucosaminyl- EXTL1 EXTL 676 proteoglycan 4-alpha-N-acetylglucosaminyltransferase) (Multiple exostosis-like protein) Q16394 EXT1_HUMAN Exostosin-1 (EC 2.4.1.224) (EC 2.4.1.225) (Glucuronosyl-N-acetylglucosaminyl- EXT1 746 proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N- acetylglucosaminyltransferase) (Multiple exostoses protein 1) (Putative tumor suppressor protein EXT1) Q9UBQ6 EXTL2_HUMAN Exostosin-like 2 (EC 2.4.1.223) (Alpha-1,4-N-acetylhexosaminyltransferase EXTL2) EXTL2 EXTR2 330 (Alpha-GalNAcT EXTL2) (EXT-related protein 2) (Glucuronyl-galactosyl-proteoglycan 4- alpha-N-acetylglucosaminyltransferase) [Cleaved into: Processed exostosin-like 2] Q0P6D2 FA69C_HUMAN Protein FAM69C FAM69C C18orf51 419 Q5T7M9 FA69A_HUMAN Protein FAM69A FAM69A 428 Q9H9S5 FKRP_HUMAN Fukutin-related protein (EC 2.—.—.—) FKRP 495 Q8N539 FBCD1_HUMAN Fibrinogen C domain-containing protein 1 FIBCD1 461 UNQ701/PRO1346 P06734 FCER2_HUMAN Low affinity immunoglobulin epsilon Fc receptor (BLAST-2) (C-type lectin domain family 4 FCER2 CD23A 321 member J) (Fc-epsilon-RII) (Immunoglobulin E-binding factor) (Lymphocyte IgE receptor) CLEC4J FCE2 (CD antigen CD23) [Cleaved into: Low affinity immunoglobulin epsilon Fc receptor IGEBF membrane-bound form; Low affinity immunoglobulin epsilon Fc receptor soluble form] O75072 FKTN_HUMAN Fukutin (EC 2.—.—.—) (Fukuyama-type congenital muscular dystrophy protein) FKTN FCMD 461 Q04609 FOLH1_HUMAN Glutamate carboxypeptidase 2 (EC 3.4.17.21) (Cell growth-inhibiting gene 27 protein) FOLH1 FOLH 750 (Folate hydrolase 1) (Folylpoly-gamma-glutamate carboxypeptidase) (FGCP) (Glutamate NAALAD1 PSM carboxypeptidase II) (GCPII) (Membrane glutamate carboxypeptidase) (mGCP) (N- PSMA GIG27 acetylated-alpha-linked acidic dipeptidase I) (NAALADase I) (Prostate-specific membrane antigen) (PSM) (PSMA) (Pteroylpoly-gamma-glutamate carboxypeptidase) Q9BYC5 FUT8_HUMAN Alpha-(1,6)-fucosyltransferase (Alpha1-6FucT) (EC 2.4.1.68) (Fucosyltransferase 8) FUT8 575 (GDP-L-Fuc: N-acetyl-beta-D-glucosaminide alpha1,6-fucosyltransferase) (GDP-fucose-- glycoprotein fucosyltransferase) (Glycoprotein 6-alpha-L-fucosyltransferase) P19526 FUT1_HUMAN Galactoside 2-alpha-L-fucosyltransferase 1 (EC 2.4.1.69) (Alpha(1,2)FT 1) (Blood group FUT1 H HSC 365 H alpha 2-fucosyltransferase) (Fucosyltransferase 1) (GDP-L-fucose: beta-D-galactoside 2-alpha-L-fucosyltransferase 1) P51993 FUT6_HUMAN Alpha-(1,3)-fucosyltransferase 6 (EC 2.4.1.65) (Fucosyltransferase 6) FUT6 FCT3A 359 (Fucosyltransferase VI) (Fuc-TVI) (FucT-VI) (Galactoside 3-L-fucosyltransferase) Q9H3Q3 G3ST2_HUMAN Galactose-3-O-sulfotransferase 2 (Gal3ST-2) (EC 2.8.2.—) (Beta-galactose-3-O- GAL3ST2 GP3ST 398 sulfotransferase 2) (Gal-beta-1,3-GalNAc 3′-sulfotransferase 2) (Glycoprotein beta-Gal 3′-sulfotransferase 2) Q10981 FUT2_HUMAN Galactoside 2-alpha-L-fucosyltransferase 2 (EC 2.4.1.69) (Alpha(1,2)FT 2) FUT2 SEC2 343 (Fucosyltransferase 2) (GDP-L-fucose: beta-D-galactoside 2-alpha-L-fucosyltransferase 2) (SE2) (Secretor blood group alpha-2-fucosyltransferase) (Secretor factor) (Se) P22083 FUT4_HUMAN Alpha-(1,3)-fucosyltransferase 4 (EC 2.4.1.—) (ELAM-1 ligand fucosyltransferase) FUT4 ELFT FCT3A 530 (Fucosyltransferase 4) (Fucosyltransferase IV) (Fuc-TIV) (FucT-IV) (Galactoside 3-L- fucosyltransferase) Q96A11 G3ST3_HUMAN Galactose-3-O-sulfotransferase 3 (Gal3ST-3) (EC 2.8.2.—) (Beta-galactose-3-O- GAL3ST3 431 sulfotransferase 3) (Gal3ST3) (Gal-beta-1,3-GalNAc 3′-sulfotransferase 3) Q10472 GALT1_HUMAN Polypeptide N-acetylgalactosaminyltransferase 1 (EC 2.4.1.41) (Polypeptide GalNAc GALNT1 559 transferase 1) (GalNAc-T1) (pp-GaNTase 1) (Protein-UDP acetylgalactosaminyltransferase 1) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 1) [Cleaved into: Polypeptide N- acetylgalactosaminyltransferase 1 soluble form] Q10471 GALT2_HUMAN Polypeptide N-acetylgalactosaminyltransferase 2 (EC 2.4.1.41) (Polypeptide GalNAc GALNT2 571 transferase 2) (GalNAc-T2) (pp-GaNTase 2) (Protein-UDP acetylgalactosaminyltransferase 2) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 2) [Cleaved into: Polypeptide N- acetylgalactosaminyltransferase 2 soluble form] Q14435 GALT3_HUMAN Polypeptide N-acetylgalactosaminyltransferase 3 (EC 2.4.1.41) (Polypeptide GalNAc GALNT3 633 transferase 3) (GalNAc-T3) (pp-GaNTase 3) (Protein-UDP acetylgalactosaminyltransferase 3) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 3) Q8NCL4 GALT6_HUMAN Polypeptide N-acetylgalactosaminyltransferase 6 (EC 2.4.1.41) (Polypeptide GalNAc GALNT6 622 transferase 6) (GalNAc-T6) (pp-GaNTase 6) (Protein-UDP acetylgalactosaminyltransferase 6) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 6) Q6P4F1 FUT10_HUMAN Alpha-(1,3)-fucosyltransferase 10 (EC 2.4.1.—) (Fucosyltransferase X) (Fuc-TX) (FucT-X) FUT10 479 (Galactoside 3-L-fucosyltransferase 10) (Fucosyltransferase 10) Q99999 G3ST1_HUMAN Galactosylceramide sulfotransferase (GalCer sulfotransferase) (EC 2.8.2.11) (3′- GAL3ST1 CST 423 phosphoadenosine-5′-phosphosulfate: GalCer sulfotransferase) (3′- phosphoadenylylsulfate: galactosylceramide 3′-sulfotransferase) (Cerebroside sulfotransferase) Q96RP7 G3ST4_HUMAN Galactose-3-O-sulfotransferase 4 (Gal3ST-4) (EC 2.8.2.—) (Beta-galactose-3-O- GAL3ST4 PP6968 486 sulfotransferase 4) (Gal-beta-1,3-GalNAc 3′-sulfotransferase) Q9NY28 GALT8_HUMAN Probable polypeptide N-acetylgalactosaminyltransferase 8 (EC 2.4.1.41) (Polypeptide GALNT8 637 GalNAc transferase 8) (GalNAc-T8) (pp-GaNTase 8) (Protein-UDP acetylgalactosaminyltransferase 8) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 8) Q9HCQ5 GALT9_HUMAN Polypeptide N-acetylgalactosaminyltransferase 9 (EC 2.4.1.41) (Polypeptide GalNAc GALNT9 603 transferase 9) (GalNAc-T9) (pp-GaNTase 9) (Protein-UDP acetylgalactosaminyltransferase 9) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 9) Q495W5 FUT11_HUMAN Alpha-(1,3)-fucosyltransferase 11 (EC 2.4.1.—) (Fucosyltransferase XI) (Fuc-TXI) (FucT- FUT11 492 XI) (Galactoside 3-L-fucosyltransferase 11) (Fucosyltransferase 11) P21217 FUT3_HUMAN Galactoside 3(4)-L-fucosyltransferase (EC 2.4.1.65) (Blood group Lewis alpha-4- FUT3 FT3B LE 361 fucosyltransferase) (Lewis FT) (Fucosyltransferase 3) (Fucosyltransferase III) (FucT-III) Q9Y231 FUT9_HUMAN Alpha-(1,3)-fucosyltransferase 9 (EC 2.4.1.—) (Fucosyltransferase 9) (Fucosyltransferase FUT9 359 IX) (Fuc-TIX) (FucT-IX) (Galactoside 3-L-fucosyltransferase) Q7Z7M9 GALT5_HUMAN Polypeptide N-acetylgalactosaminyltransferase 5 (EC 2.4.1.41) (Polypeptide GalNAc GALNT5 940 transferase 5) (GalNAc-T5) (pp-GaNTase 5) (Protein-UDP acetylgalactosaminyltransferase 5) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 5) Q9P109 GCNT4_HUMAN Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 4 GCNT4 453 (EC 2.4.1.102) (Core 2-branching enzyme 3) (Core2-GlcNAc-transferase 3) (C2GnT3) Q6ZNI0 GCNT7_HUMAN Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 7 GCNT7 C20orf105 430 (EC 2.4.1.—) Q11128 FUT5_HUMAN Alpha-(1,3)-fucosyltransferase 5 (EC 2.4.1.65) (Fucosyltransferase 5) FUT5 374 (Fucosyltransferase V) (Fuc-TV) (FucT-V) (Galactoside 3-L-fucosyltransferase) Q11130 FUT7_HUMAN Alpha-(1,3)-fucosyltransferase 7 (EC 2.4.1.—) (Fucosyltransferase 7) (Fucosyltransferase FUT7 342 VII) (Fuc-TVII) (FucT-VII) (Galactoside 3-L-fucosyltransferase) (Selectin ligand synthase) Q02742 GCNT1_HUMAN Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase GCNT1 NACGT2 428 (EC 2.4.1.102) (Core 2-branching enzyme) (Core2-GlcNAc-transferase) (C2GNT) (Core 2 GNT) Q8N5D6 GBGT1_HUMAN Globoside alpha-1,3-N-acetylgalactosaminyltransferase 1 (EC 2.4.1.—) (Forssman GBGT1 347 glycolipid synthase-like protein) UNQ2513/PRO6002 Q5T4J0 GCNT6_HUMAN Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 6 GCNT6 391 (EC 2.4.1.—) Q4G0N0 GGTA1_HUMAN Inactive N-acetyllactosaminide alpha-1,3-galactosyltransferase (Glycoprotein alpha- GGTA1P GGTA1 100 galactosyltransferase 1 pseudogene) Q68CQ7 GL8D1_HUMAN Glycosyltransferase 8 domain-containing protein 1 (EC 2.4.1.—) GLT8D1 GALA4A 371 AD-017 MSTP137 UNQ572/PRO1134 Q8N4A0 GALT4_HUMAN Polypeptide N-acetylgalactosaminyltransferase 4 (EC 2.4.1.41) (Polypeptide GalNAc GALNT4 578 transferase 4) (GalNAc-T4) (pp-GaNTase 4) (Protein-UDP acetylgalactosaminyltransferase 4) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 4) Q86SF2 GALT7_HUMAN N-acetylgalactosaminyltransferase 7 (EC 2.4.1.—) (Polypeptide GalNAc transferase 7) GALNT7 657 (GalNAc-T7) (pp-GaNTase 7) (Protein-UDP acetylgalactosaminyltransferase 7) (UDP- GalNAc: polypeptide N-acetylgalactosaminyltransferase 7) O95395 GCNT3_HUMAN Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 3 GCNT3 438 (EC 2.4.1.102) (EC 2.4.1.150) (C2GnT-mucin type) (C2GnT-M) (hC2GnT-M) (Core 2/core 4 beta-1,6-N-acetylglucosaminyltransferase) (C2/4GnT) P19440 GGT1_HUMAN Gamma-glutamyltranspeptidase 1 (GGT 1) (EC 2.3.2.2) (Gamma-glutamyltransferase 1) GGT1 GGT 569 (Glutathione hydrolase 1) (EC 3.4.19.13) (Leukotriene-C4 hydrolase) (EC 3.4.19.14) (CD antigen CD224) [Cleaved into: Gamma-glutamyltranspeptidase 1 heavy chain; Gamma- glutamyltranspeptidase 1 light chain] Q7Z4J2 GL6D1_HUMAN Glycosyltransferase 6 domain-containing protein 1 (EC 2.4.1.—) (Galactosyltransferase GLT6D1 GLTDC1 308 family 6 domain-containing 1) GT6M7 O94923 GLCE_HUMAN D-glucuronyl C5-epimerase (EC 5.1.3.17) (Heparan sulfate C5-epimerase) (Hsepi) GLCE KIAA0836 617 (Heparin/heparan sulfate: glucuronic acid C5-epimerase) (Heparosan-N-sulfate- glucuronate 5-epimerase) Q86SR1 GLT10_HUMAN Polypeptide N-acetylgalactosaminyltransferase 10 (EC 2.4.1.41) (Polypeptide GalNAc GALNT10 603 transferase 10) (GalNAc-T10) (pp-GaNTase 10) (Protein-UDP acetylgalactosaminyltransferase 10) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 10) Q8IXK2 GLT12_HUMAN Polypeptide N-acetylgalactosaminyltransferase 12 (EC 2.4.1.41) (Polypeptide GalNAc GALNT12 581 transferase 12) (GalNAc-T12) (pp-GaNTase 12) (Protein-UDP acetylgalactosaminyltransferase 12) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 12) Q96FL9 GLT14_HUMAN Polypeptide N-acetylgalactosaminyltransferase 14 (EC 2.4.1.41) (Polypeptide GalNAc GALNT14 552 transferase 14) (GalNAc-T14) (pp-GaNTase 14) (Protein-UDP UNQ2434/PRO4994 acetylgalactosaminyltransferase 14) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 14) Q8N428 GLT16_HUMAN Polypeptide N-acetylgalactosaminyltransferase 16 (EC 2.4.1.41) (Polypeptide GalNAc GALNT16 GALNTL1 558 transferase 16) (GalNAc-T16) (Polypeptide GalNAc transferase-like protein 1) (GalNAc-T- KIAA1130 like protein 1) (pp-GaNTase-like protein 1) (Polypeptide N- acetylgalactosaminyltransferase-like protein 1) (Protein-UDP acetylgalactosaminyltransferase-like protein 1) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase-like protein 1) P36269 GGT5_HUMAN Gamma-glutamyltransferase 5 (GGT 5) (EC 2.3.2.2) (Gamma-glutamyl transpeptidase- GGT5 GGTLA1 586 related enzyme) (GGT-rel) (Gamma-glutamyltransferase-like activity 1) (Gamma- glutamyltranspeptidase 5) (Glutathione hydrolase 5) (EC 3.4.19.13) (Leukotriene-C4 hydrolase) (EC 3.4.19.14) [Cleaved into: Gamma-glutamyltransferase 5 heavy chain; Gamma-glutamyltransferase 5 light chain] Q6P531 GGT6_HUMAN Gamma-glutamyltransferase 6 (GGT 6) (EC 2.3.2.2) (Gamma-glutamyltranspeptidase 6) GGT6 493 (Glutathione hydrolase 6) (EC 3.4.19.13) [Cleaved into: Gamma-glutamyltransferase 6 heavy chain; Gamma-glutamyltransferase 6 light chain] Q9UJ14 GGT7_HUMAN Gamma-glutamyltransferase 7 (GGT 7) (EC 2.3.2.2) (Gamma-glutamyltransferase-like 3) GGT7 GGTL3 662 (Gamma-glutamyltransferase-like 5) (Gamma-glutamyltranspeptidase 7) (Glutathione GGTL5 hydrolase 7) (EC 3.4.19.13) [Cleaved into: Gamma-glutamyltransferase 7 heavy chain; Gamma-glutamyltransferase 7 light chain] Q6ZMI3 GLDN_HUMAN Gliomedin [Cleaved into: Gliomedin shedded ectodomain] GLDN COLM 551 UNQ9339/PRO34011 Q8IUC8 GLT13_HUMAN Polypeptide N-acetylgalactosaminyltransferase 13 (EC 2.4.1.41) (Polypeptide GalNAc GALNT13 KIAA1918 556 transferase 13) (GalNAc-T13) (pp-GaNTase 13) (Protein-UDP acetylgalactosaminyltransferase 13) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 13) Q6P9A2 GLT18_HUMAN Polypeptide N-acetylgalactosaminyltransferase 18 (EC 2.4.1.41) (Polypeptide GalNAc GALNT18 GALNTL4 607 transferase 18) (GalNAc-T18) (Polypeptide GalNAc transferase-like protein 4) (GalNAc-T- like protein 4) (pp-GaNTase-like protein 4) (Polypeptide N- acetylgalactosaminyltransferase-like protein 4) (Protein-UDP acetylgalactosaminyltransferase-like protein 4) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase-like protein 4) Q49A17 GLTL6_HUMAN Polypeptide N-acetylgalactosaminyltransferase-like 6 (EC 2.4.1.41) (Polypeptide GalNAc GALNTL6 GALNT17 601 transferase 17) (GalNAc-T17) (pp-GaNTase 17) (Protein-UDP acetylgalactosaminyltransferase 17) (Putative polypeptide N- acetylgalactosaminyltransferase 17) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 17) Q3T906 GNPTA_HUMAN N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (EC 2.7.8.17) (GlcNAc- GNPTAB GNPTA 1256 1-phosphotransferase subunits alpha/beta) (Stealth protein GNPTAB) (UDP-N- KIAA1208 acetylglucosamine-1-phosphotransferase subunits alpha/beta) [Cleaved into: N- acetylglucosamine-1-phosphotransferase subunit alpha; N-acetylglucosamine-1- phosphotransferase subunit beta] A6NGU5 GGT3_HUMAN Putative gamma-glutamyltranspeptidase 3 (GGT 3) (EC 2.3.2.2) (Gamma- GGT3P GGT3 568 glutamyltransferase 3) (Glutathione hydrolase 3) (EC 3.4.19.13) [Cleaved into: Putative gamma-glutamyltranspeptidase 3 heavy chain; Putative gamma-glutamyltranspeptidase 3 light chain] Q9H1C3 GL8D2_HUMAN Glycosyltransferase 8 domain-containing protein 2 (EC 2.4.1.—) GLT8D2 GALA4A 349 UNQ1901/PRO4347 Q8N3T1 GLT15_HUMAN Polypeptide N-acetylgalactosaminyltransferase 15 (EC 2.4.1.41) (Polypeptide GalNAc GALNT15 GALNTL2 639 transferase-like protein 2) (GalNAc-T-like protein 2) (pp-GaNTase-like protein 2) UNQ770/PRO1564 (Polypeptide N-acetylgalactosaminyltransferase-like protein 2) (Protein-UDP acetylgalactosaminyltransferase-like protein 2) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase-like protein 2) Q6IS24 GLTL3_HUMAN Putative polypeptide N-acetylgalactosaminyltransferase-like protein 3 (EC 2.4.1.41) WBSCR17 598 (Polypeptide GalNAc transferase-like protein 3) (GalNAc-T-like protein 3) (pp-GaNTase- GALNTL3 like protein 3) (Protein-UDP acetylgalactosaminyltransferase-like protein 3) (UDP- GalNAc: polypeptide N-acetylgalactosaminyltransferase-like protein 3) (Williams-Beuren syndrome chromosomal region 17 protein) Q8NCW6 GLT11_HUMAN Polypeptide N-acetylgalactosaminyltransferase 11 (EC 2.4.1.41) (Polypeptide GalNAc GALNT11 608 transferase 11) (GalNAc-T11) (pp-GaNTase 11) (Protein-UDP acetylgalactosaminyltransferase 11) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 11) Q7Z4T8 GLTL5_HUMAN Inactive polypeptide N-acetylgalactosaminyltransferase-like protein 5 (Polypeptide GALNTL5 GALNT15 443 GalNAc transferase 15) (GalNAc-T15) (pp-GaNTase 15) (Protein-UDP acetylgalactosaminyltransferase 15) (UDP-GalNAc: polypeptide N- acetylgalactosaminyltransferase 15) Q8N0V5 GNT2A_HUMAN N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (N- GCNT2 GCNT5 II 402 acetylglucosaminyltransferase) (EC 2.4.1.150) (I-branching enzyme) (IGNT) NACGT1 O00461 GOLI4_HUMAN Golgi integral membrane protein 4 (Golgi integral membrane protein, cis) (GIMPc) (Golgi GOLIM4 GIMPC 696 phosphoprotein 4) (Golgi-localized phosphoprotein of 130 kDa) (Golgi phosphoprotein of GOLPH4 GPP130 130 kDa) Q8NBJ4 GOLM1_HUMAN Golgi membrane protein 1 (Golgi membrane protein GP73) (Golgi phosphoprotein 2) GOLM1 C9orf155 401 GOLPH2 PSEC0242 UNQ686/PRO1326 A0PJZ3 GXLT2_HUMAN Glucoside xylosyltransferase 2 (EC 2.4.2.n2) (Glycosyltransferase 8 domain-containing GXYLT2 GLT8D4 443 protein 4) Q4G148 GXLT1_HUMAN Glucoside xylosyltransferase 1 (EC 2.4.2.n2) (Glycosyltransferase 8 domain-containing GXYLT1 GLT8D3 440 protein 3) Q96MM7 H6ST2_HUMAN Heparan-sulfate 6-O-sulfotransferase 2 (HS6ST-2) (EC 2.8.2.—) HS6ST2 PSEC0092 605 O60243 H6ST1_HUMAN Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST-1) (EC 2.8.2.—) HS6ST1 HS6ST 411 Q8IZP7 H6ST3_HUMAN Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST-3) (EC 2.8.2.—) HS6ST3 471 P04233 HG2A_HUMAN HLA class II histocompatibility antigen gamma chain (HLA-DR antigens-associated CD74 DHLAG 296 invariant chain) (Ia antigen-associated invariant chain) (Ii) (p33) (CD antigen CD74) Q7LGA3 HS2ST_HUMAN Heparan sulfate 2-O-sulfotransferase 1 (2-O-sulfotransferase) (2OST) (EC 2.8.2.—) HS2ST1 HS2ST 356 KIAA0448 Q8IZT8 HS3S5_HUMAN Heparan sulfate glucosamine 3-O-sulfotransferase 5 (EC 2.8.2.23) (Heparan sulfate D- HS3ST5 3OST5 346 glucosaminyl 3-O-sulfotransferase 5) (3-OST-5) (Heparan sulfate 3-O-sulfotransferase 5) HS3OST5 (h3-OST-5) P05981 HEPS_HUMAN Serine protease hepsin (EC 3.4.21.106) (Transmembrane protease serine 1) [Cleaved HPN TMPRSS1 417 into: Serine protease hepsin non-catalytic chain; Serine protease hepsin catalytic chain] Q9Y663 HS3SA_HUMAN Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (EC 2.8.2.30) (Heparan sulfate D- HS3ST3A1 406 glucosaminyl 3-O-sulfotransferase 3A1) (3-OST-3A) (Heparan sulfate 3-O- 3OST3A1 HS3ST3A sulfotransferase 3A1) (h3-OST-3A) UNQ2551/PRO6180 Q9Y278 HS3S2_HUMAN Heparan sulfate glucosamine 3-O-sulfotransferase 2 (EC 2.8.2.29) (Heparan sulfate D- HS3ST2 3OST2 367 glucosaminyl 3-O-sulfotransferase 2) (3-OST-2) (Heparan sulfate 3-O-sulfotransferase 2) UNQ2442/PRO5004 (h3-OST-2) Q9Y661 HS3S4_HUMAN Heparan sulfate glucosamine 3-O-sulfotransferase 4 (EC 2.8.2.23) (Heparan sulfate D- HS3ST4 3OST4 456 glucosaminyl 3-O-sulfotransferase 4) (3-OST-4) (Heparan sulfate 3-O-sulfotransferase 4) (h3-OST-4) Q96QI5 HS3S6_HUMAN Heparan sulfate glucosamine 3-O-sulfotransferase 6 (EC 2.8.2.23) (Heparan sulfate D- HS3ST6 HS3ST5 342 glucosaminyl 3-O-sulfotransferase 6) (3-OST-6) (Heparan sulfate 3-O-sulfotransferase 6) (h3-OST-6) Q9Y662 HS3SB_HUMAN Heparan sulfate glucosamine 3-O-sulfotransferase 3B1 (EC 2.8.2.30) (Heparan sulfate D- HS3ST3B1 390 glucosaminyl 3-O-sulfotransferase 3B1) (3-OST-3B) (Heparan sulfate 3-O- 3OST3B1 HS3ST3B sulfotransferase 3B1) (h3-OST-3B) P07099 HYEP_HUMAN Epoxide hydrolase 1 (EC 3.3.2.9) (Epoxide hydratase) (Microsomal epoxide hydrolase) EPHX1 EPHX 455 EPOX P46695 IEX1_HUMAN Radiation-inducible immediate-early gene IEX-1 (Differentiation-dependent gene 2 IER3 DIF2 IEX1 156 protein) (Protein DIF-2) (Immediate early protein GLY96) (Immediate early response 3 PRG1 protein) (PACAP-responsive gene 1 protein) (Protein PRG1) P55073 IOD3_HUMAN Thyroxine 5-deiodinase (EC 1.21.99.3) (5DIII) (DIOIII) (Type 3 DI) (Type III iodothyronine DIO3 ITDI3 TXDI3 304 deiodinase) Q9NX62 IMPA3_HUMAN Inositol monophosphatase 3 (IMP 3) (IMPase 3) (EC 3.1.3.25) (EC 3.1.3.7) (Golgi 3- IMPAD1 IMPA3 359 prime phosphoadenosine 5-prime phosphate 3-prime phosphatase) (Golgi-resident PAP phosphatase) (gPAPP) (Inositol monophosphatase domain-containing protein 1) (Inositol- 1(or 4)-monophosphatase 3) (Myo-inositol monophosphatase A3) Q01628 IFM3_HUMAN Interferon-induced transmembrane protein 3 (Dispanin subfamily A member 2b) IFITM3 133 (DSPA2b) (Interferon-inducible protein 1-8U) Q9NQX7 ITM2C_HUMAN Integral membrane protein 2C (Cerebral protein 14) (Transmembrane protein BRI3) ITM2C BRI3 hucep- 267 [Cleaved into: CT-BRI3] 14 NPD018 PSEC0047 O43736 ITM2A_HUMAN Integral membrane protein 2A (Protein E25) ITM2A 263 UNQ603/PRO1189 Q6NSJ0 K1161_HUMAN Uncharacterized family 31 glucosidase KIAA1161 (EC 3.2.1.—) KIAA1161 714 Q9Y287 ITM2B_HUMAN Integral membrane protein 2B (Immature BRI2) (imBRI2) (Protein E25B) ITM2B BRI BRI2 266 (Transmembrane protein BRI) (Bri) [Cleaved into: BRI2, membrane form (Mature BRI2) (mBRI2); BRI2 intracellular domain (BRI2 ICD); BRI2C, soluble form; Bri23 peptide (Bri2- 23) (ABri23) (C-terminal peptide) (P23 peptide)] Q9NZS2 KLRF1_HUMAN Killer cell lectin-like receptor subfamily F member 1 (Lectin-like receptor F1) (Activating KLRF1 CLEC5C ML 232 coreceptor NKp80) (C-type lectin domain family 5 member C) P23276 KELL_HUMAN Kell blood group glycoprotein (EC 3.4.24.—) (CD antigen CD238) KEL 732 Q5H943 KKLC1_HUMAN Kita-kyushu lung cancer antigen 1 (KK-LC-1) (Cancer/testis antigen 83) CT83 CXorf61 113 KKLC1 Q13241 KLRD1_HUMAN Natural killer cells antigen CD94 (KP43) (Killer cell lectin-like receptor subfamily D KLRD1 CD94 179 member 1) (NK cell receptor) (CD antigen CD94) Q8N3Y3 LARG2_HUMAN Glycosyltransferase-like protein LARGE2 (EC 2.4.—.—) (Glycosyltransferase-like 1B) GYLTL1B LARGE2 721 [Includes: Xylosyltransferase LARGE2 (EC 2.4.2.—); Beta-1,3-glucuronyltransferase PP5656 LARGE2 (EC 2.4.1.—)] Q12918 KLRB1_HUMAN Killer cell lectin-like receptor subfamily B member 1 (C-type lectin domain family 5 KLRB1 CLEC5B 225 member B) (HNKR-P1a) (NKR-P1A) (Natural killer cell surface protein P1A) (CD antigen NKRP1A CD161) Q96E93 KLRG1_HUMAN Killer cell lectin-like receptor subfamily G member 1 (C-type lectin domain family 15 KLRG1 CLEC15A 195 member A) (ITIM-containing receptor MAFA-L) (MAFA-like receptor) (Mast cell function- MAFA MAFAL associated antigen) Q9UIQ6 LCAP_HUMAN Leucyl-cystinyl aminopeptidase (Cystinyl aminopeptidase) (EC 3.4.11.3) (Insulin- LNPEP OTASE 1025 regulated membrane aminopeptidase) (Insulin-responsive aminopeptidase) (IRAP) (Oxytocinase) (OTase) (Placental leucine aminopeptidase) (P-LAP) [Cleaved into: Leucyl- cystinyl aminopeptidase, pregnancy serum form] O95461 LARGE_HUMAN Glycosyltransferase-like protein LARGE1 (EC 2.4.—.—) (Acetylglucosaminyltransferase-like LARGE KIAA0609 756 1A) [Includes: Xylosyltransferase LARGE (EC 2.4.2.—); Beta-1,3-glucuronyltransferase LARGE1 LARGE (EC 2.4.1.—)] D3W0D1 KLRF2_HUMAN Killer cell lectin-like receptor subfamily F member 2 (Lectin-like receptor F2) (Activating KLRF2 207 coreceptor NKp65) Q86UP2 KTN1_HUMAN Kinectin (CG-1 antigen) (Kinesin receptor) KTN1 CG1 1357 KIAA0004 P42167 LAP2B_HUMAN Lamina-associated polypeptide 2, isoforms beta/gamma (Thymopoietin, isoforms TMPO LAP2 454 beta/gamma) (TP beta/gamma) (Thymopoietin-related peptide isoforms beta/gamma) (TPRP isoforms beta/gamma) [Cleaved into: Thymopoietin (TP) (Splenin); Thymopentin (TP5)] Q8NES3 LFNG_HUMAN Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (EC 2.4.1.222) (O-fucosylpeptide LFNG 379 3-beta-N-acetylglucosaminyltransferase) Q96AG4 LRC59_HUMAN Leucine-rich repeat-containing protein 59 (Ribosome-binding protein p34) (p34) LRRC59 PRO1855 307 Q5SRI9 MANEA_HUMAN Glycoprotein endo-alpha-1,2-mannosidase (Endo-alpha mannosidase) MANEA 462 (Endomannosidase) (hEndo) (EC 3.2.1.130) (Mandaselin) Q5VSG8 MANEL_HUMAN Glycoprotein endo-alpha-1,2-mannosidase-like protein (EC 3.2.1.—) MANEAL 457 Q5VT66 MARC1_HUMAN Mitochondrial amidoxime-reducing component 1 (mARC1) (EC 1.—.—.—) (Molybdenum MARC1 MOSC1 337 cofactor sulfurase C-terminal domain-containing protein 1) (MOSC domain-containing protein 1) (Moco sulfurase C-terminal domain-containing protein 1) Q9UKM7 MA1B1_HUMAN Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (EC 3.2.1.113) MAN1B1 699 (ER alpha-1,2-mannosidase) (ER mannosidase 1) (ERMan1) (Man9GlcNAc2-specific- UNQ747/PRO1477 processing alpha-mannosidase) (Mannosidase alpha class 1B member 1) Q16706 MA2A1_HUMAN Alpha-mannosidase 2 (EC 3.2.1.114) (Golgi alpha-mannosidase II) (AMan II) (Man II) MAN2A1 MANA2 1144 (Mannosidase alpha class 2A member 1) (Mannosyl-oligosaccharide 1,3-1,6-alpha- mannosidase) P49641 MA2A2_HUMAN Alpha-mannosidase 2x (EC 3.2.1.114) (Alpha-mannosidase IIx) (Man IIx) (Mannosidase MAN2A2 MANA2X 1150 alpha class 2A member 2) (Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase) P33908 MA1A1_HUMAN Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (EC 3.2.1.113) (Man(9)-alpha- MAN1A1 653 mannosidase) (Man9-mannosidase) (Mannosidase alpha class 1A member 1) (Processing alpha-1,2-mannosidase IA) (Alpha-1,2-mannosidase IA) O60476 MA1A2_HUMAN Mannosyl-oligosaccharide 1,2-alpha-mannosidase IB (EC 3.2.1.113) (Mannosidase alpha MAN1A2 MAN1B 641 class 1A member 2) (Processing alpha-1,2-mannosidase IB) (Alpha-1,2-mannosidase IB) Q9NR34 MA1C1_HUMAN Mannosyl-oligosaccharide 1,2-alpha-mannosidase IC (EC 3.2.1.113) (HMIC) MAN1C1 MAN1A3 630 (Mannosidase alpha class 1C member 1) (Processing alpha-1,2-mannosidase IC) (Alpha- MAN1C 1,2-mannosidase IC) Q9UEW3 MARCO_HUMAN Macrophage receptor MARCO (Macrophage receptor with collagenous structure) MARCO SCARA2 520 (Scavenger receptor class A member 2) O00587 MFNG_HUMAN Beta-1,3-N-acetylglucosaminyltransferase manic fringe (EC 2.4.1.222) (O-fucosylpeptide MFNG 321 3-beta-N-acetylglucosaminyltransferase) Q09327 MGAT3_HUMAN Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (EC 2.4.1.144) MGAT3 GGNT3 533 (N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase III) (GNT-III) (GlcNAc-T III) (N-acetylglucosaminyltransferase III) Q3V5L5 MGT5B_HUMAN Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase B (EC 2.4.1.—) MGAT5B KIAA2008 792 (EC 2.4.1.155) (Alpha-mannoside beta-1,6-N-acetylglucosaminyltransferase B) (GlcNAc- T Vb) (GNT-Vb) (hGnTVb) (Mannoside acetylglucosaminyltransferase 5B) (N- acetylglucosaminyl-transferase Vb) (N-acetylglucosaminyltransferase IX) (GNT-IX) Q8IX19 MCEM1_HUMAN Mast cell-expressed membrane protein 1 MCEMP1 C19orf59 187 O43451 MGA_HUMAN Maltase-glucoamylase, intestinal [Includes: Maltase (EC 3.2.1.20) (Alpha-glucosidase); MGAM MGA 1857 Glucoamylase (EC 3.2.1.3) (Glucan 1,4-alpha-glucosidase)] MGAML Q9UBM8 MGT4C_HUMAN Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase C (EC MGAT4C 478 2.4.1.145) (N-acetylglucosaminyltransferase IV homolog) (hGnT-IV-H) (N-glycosyl- oligosaccharide-glycoprotein N-acetylglucosaminyltransferase IVc) (GlcNAc-T IVc) (GnT- IVc) (N-acetylglucosaminyltransferase IVc) (UDP-N-acetylglucosamine: alpha-1,3-D- mannoside beta-1,4-N-acetylglucosaminyltransferase IVc) Q10469 MGAT2_HUMAN Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (EC 2.4.1.143) MGAT2 447 (Beta-1,2-N-acetylglucosaminyltransferase II) (GlcNAc-T II) (GNT-II) (Mannoside acetylglucosaminyltransferase 2) (N-glycosyl-oligosaccharide-glycoprotein N- acetylglucosaminyltransferase II) P26572 MGAT1_HUMAN Alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (EC 2.4.1.101) MGAT1 GGNT1 445 (N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase I) (GNT-I) GLCT1 GLYT1 (GlcNAc-T I) MGAT Q9UM21 MGT4A_HUMAN Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (EC MGAT4A 535 2.4.1.145) (N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase IVa) (GlcNAc-T IVa) (GnT-IVa) (N-acetylglucosaminyltransferase IVa) (UDP-N- acetylglucosamine: alpha-1,3-D-mannoside beta-1,4-N-acetylglucosaminyltransferase IVa) [Cleaved into: Alpha-1,3-mannosyl-glycoprotein 4-beta-N- acetylglucosaminyltransferase A soluble form] Q9UQ53 MGT4B_HUMAN Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase B (EC MGAT4B 548 2.4.1.145) (N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase IVb) UNQ906/PRO1927 (GlcNAc-T IVb) (GnT-IVb) (N-acetylglucosaminyltransferase IVb) (UDP-N- acetylglucosamine: alpha-1,3-D-mannoside beta-1,4-N-acetylglucosaminyltransferase IVb) Q9BY79 MFRP_HUMAN Membrane frizzled-related protein (Membrane-type frizzled-related protein) MFRP 579 Q495T6 MMEL1_HUMAN Membrane metallo-endopeptidase-like 1 (EC 3.4.24.11) (Membrane metallo- MMEL1 MELL1 779 endopeptidase-like 2) (NEP2(m)) (Neprilysin II) (NEPII) (Neprilysin-2) (NEP2) (NL2) MMEL2 NEP2 [Cleaved into: Membrane metallo-endopeptidase-like 1, soluble form (Neprilysin-2 secreted) (NEP2(s))] O75900 MMP23_HUMAN Matrix metalloproteinase-23 (MMP-23) (EC 3.4.24.—) (Femalysin) (MIFR-1) (Matrix MMP23A MMP21; 390 metalloproteinase-21) (MMP-21) (Matrix metalloproteinase-22) (MMP-22) [Cleaved into: MMP23B MMP21 Matrix metalloproteinase-23, soluble form] MMP22 Q09328 MGT5A_HUMAN Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A (EC MGAT5 GGNT5 741 2.4.1.155) (Alpha-mannoside beta-1,6-N-acetylglucosaminyltransferase) (GlcNAc-T V) (GNT-V) (Mannoside acetylglucosaminyltransferase 5) (N-acetylglucosaminyl-transferase V) Q13724 MOGS_HUMAN Mannosyl-oligosaccharide glucosidase (EC 3.2.1.106) (Processing A-glucosidase I) MOGS GCS1 837 P21757 MSRE_HUMAN Macrophage scavenger receptor types I and II (Macrophage acetylated LDL receptor I MSR1 SCARA1 451 and II) (Scavenger receptor class A member 1) (CD antigen CD204) Q9NZM1 MYOF_HUMAN Myoferlin (Fer-1-like protein 3) MYOF FER1L3 2061 KIAA1207 Q58DX5 NADL2_HUMAN Inactive N-acetylated-alpha-linked acidic dipeptidase-like protein 2 (NAALADase L2) NAALADL2 795 Q9Y3Q0 NALD2_HUMAN N-acetylated-alpha-linked acidic dipeptidase 2 (EC 3.4.17.21) (Glutamate NAALAD2 740 carboxypeptidase III) (GCPIII) (N-acetylated-alpha-linked acidic dipeptidase II) (NAALADase II) O95803 NDST3_HUMAN Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (EC 2.8.2.8) NDST3 HSST3 873 (Glucosaminyl N-deacetylase/N-sulfotransferase 3) (NDST-3) (hNDST-3) (N-heparan UNQ2544/PRO4998 sulfate sulfotransferase 3) (N-HSST 3) [Includes: Heparan sulfate N-deacetylase 3 (EC 3.—.—.—); Heparan sulfate N-sulfotransferase 3 (EC 2.8.2.—)] Q9UQQ1 NALDL_HUMAN N-acetylated-alpha-linked acidic dipeptidase-like protein (NAALADase L) (EC 3.4.17.21) NAALADL1 740 (100 kDa ileum brush border membrane protein) (I100) (Ileal dipeptidylpeptidase) NAALADASEL NAALADL Q9UHE5 NAT8_HUMAN N-acetyltransferase 8 (EC 2.3.1.—) (Acetyltransferase 2) (ATase2) (Camello-like protein 1) NAT8 CML1 GLA 227 (Cysteinyl-conjugate N-acetyltransferase) (CCNAT) (EC 2.3.1.80) TSC501 Q6PIU2 NCEH1_HUMAN Neutral cholesterol ester hydrolase 1 (NCEH) (EC 3.1.1.—) (Arylacetamide deacetylase- NCEH1 AADACL1 408 like 1) KIAA1363 P52848 NDST1_HUMAN Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (EC 2.8.2.8) NDST1 HSST 882 (Glucosaminyl N-deacetylase/N-sulfotransferase 1) (NDST-1) (N-heparan sulfate HSST1 sulfotransferase 1) (N-HSST 1) ([Heparan sulfate]-glucosamine N-sulfotransferase 1) (HSNST 1) [Includes: Heparan sulfate N-deacetylase 1 (EC 3.—.—.—); Heparan sulfate N- sulfotransferase 1 (EC 2.8.2.—)] P52849 NDST2_HUMAN Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 2 (EC 2.8.2.8) NDST2 HSST2 883 (Glucosaminyl N-deacetylase/N-sulfotransferase 2) (NDST-2) (N-heparan sulfate sulfotransferase 2) (N-HSST 2) [Includes: Heparan sulfate N-deacetylase 2 (EC 3.—.—.—); Heparan sulfate N-sulfotransferase 2 (EC 2.8.2.—)] Q9H3R1 NDST4_HUMAN Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (EC 2.8.2.8) NDST4 HSST4 872 (Glucosaminyl N-deacetylase/N-sulfotransferase 4) (NDST-4) (N-heparan sulfate sulfotransferase 4) (N-HSST 4) [Includes: Heparan sulfate N-deacetylase 4 (EC 3.—.—.—); Heparan sulfate N-sulfotransferase 4 (EC 2.8.2.—)] P26717 NKG2C_HUMAN NKG2-C type II integral membrane protein (CD159 antigen-like family member C) (NK KLRC2 NKG2C 231 cell receptor C) (NKG2-C-activating NK receptor) (CD antigen CD159c) P26718 NKG2D_HUMAN NKG2-D type II integral membrane protein (Killer cell lectin-like receptor subfamily K KLRK1 D12S2489E 216 member 1) (NK cell receptor D) (NKG2-D-activating NK receptor) (CD antigen CD314) NKG2D Q9UHF3 NAT8B_HUMAN Putative N-acetyltransferase 8B (EC 2.3.1.—) (Acetyltransferase 1) (ATase1) (Camello-like NAT8B CML2 227 protein 2) P08473 NEP_HUMAN Neprilysin (EC 3.4.24.11) (Atriopeptidase) (Common acute lymphocytic leukemia antigen) MME EPN 750 (CALLA) (Enkephalinase) (Neutral endopeptidase 24.11) (NEP) (Neutral endopeptidase) (Skin fibroblast elastase) (SFE) (CD antigen CD10) P26715 NKG2A_HUMAN NKG2-A/NKG2-B type II integral membrane protein (CD159 antigen-like family member KLRC1 NKG2A 233 A) (NK cell receptor A) (NKG2-A/B-activating NK receptor) (CD antigen CD159a) Q14494 NF2L1_HUMAN Nuclear factor erythroid 2-related factor 1 (NF-E2-related factor 1) (NFE2-related factor 1) NFE2L1 HBZ17 772 (Locus control region-factor 1) (Nuclear factor, erythroid derived 2, like 1) (Transcription NRF1 TCF11 factor 11) (TCF-11) (Transcription factor HBZ17) (Transcription factor LCR-F1) O43908 NKG2F_HUMAN NKG2-F type II integral membrane protein (NK cell receptor F) (NKG2-F-activating NK KLRC4 NKG2F 158 receptor) P42857 NSG1_HUMAN Neuron-specific protein family member 1 (Brain neuron cytoplasmic protein 1) NSG1 D4S234 185 Q07444 NKG2E_HUMAN NKG2-E type II integral membrane protein (NK cell receptor E) (NKG2-E-activating NK KLRC3 NKG2E 240 receptor) Q9Y328 NSG2_HUMAN Neuron-specific protein family member 2 (Protein p19) (Hmp19) NSG2 171 O95502 NPTXR_HUMAN Neuronal pentraxin receptor NPTXR 500 Q6PK18 OGFD3_HUMAN 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 3 (EC 1.14.11.—) OGFOD3 C17orf101 319 Q9NXG6 P4HTM_HUMAN Transmembrane prolyl 4-hydroxylase (P4H-TM) (EC 1.14.11.—) (Hypoxia-inducible factor P4HTM PH4 502 prolyl hydroxylase 4) (HIF-PH4) (HIF-prolyl hydroxylase 4) (HPH-4) Q9HC10 OTOF_HUMAN Otoferlin (Fer-1-like protein 2) OTOF FER1L2 1997 P78380 OLR1_HUMAN Oxidized low-density lipoprotein receptor 1 (Ox-LDL receptor 1) (C-type lectin domain OLR1 CLEC8A 273 family 8 member A) (Lectin-like oxidized LDL receptor 1) (LOX-1) (Lectin-like oxLDL LOX1 receptor 1) (hLOX-1) (Lectin-type oxidized LDL receptor 1) [Cleaved into: Oxidized low- density lipoprotein receptor 1, soluble form] Q8NF37 PCAT1_HUMAN Lysophosphatidylcholine acyltransferase 1 (LPC acyltransferase 1) (LPCAT-1) (LysoPC LPCAT1 AYTL2 534 acyltransferase 1) (EC 2.3.1.23) (1-acylglycerophosphocholine O-acyltransferase) (1- PFAAP3 alkylglycerophosphocholine O-acetyltransferase) (EC 2.3.1.67) (Acetyl-CoA: lyso-platelet- activating factor acetyltransferase) (Acetyl-CoA: lyso-PAF acetyltransferase) (Lyso-PAF acetyltransferase) (LysoPAFAT) (Acyltransferase-like 2) (Phosphonoformate immuno- associated protein 3) Q7L5N7 PCAT2_HUMAN Lysophosphatidylcholine acyltransferase 2 (LPC acyltransferase 2) (LPCAT-2) (LysoPC LPCAT2 AGPAT11 544 acyltransferase 2) (EC 2.3.1.23) (1-acylglycerol-3-phosphate O-acyltransferase 11) (1- AYTL1 AGP acyltransferase 11) (1-AGPAT 11) (EC 2.3.1.51) (1-acylglycerophosphocholine O- acyltransferase) (1-alkylglycerophosphocholine O-acetyltransferase) (EC 2.3.1.67) (Acetyl-CoA: lyso-platelet-activating factor acetyltransferase) (Acetyl-CoA: lyso-PAF acetyltransferase) (Lyso-PAF acetyltransferase) (LysoPAFAT) (Acyltransferase-like 1) (Lysophosphatidic acid acyltransferase alpha) (LPAAT-alpha) Q7Z412 PEX26_HUMAN Peroxisome assembly protein 26 (Peroxin-26) PEX26 305 Q9NST1 PLPL3_HUMAN Patatin-like phospholipase domain-containing protein 3 (EC 3.1.1.3) (Acylglycerol O- PNPLA3 ADPN 481 acyltransferase) (EC 2.3.1.—) (Adiponutrin) (Calcium-independent phospholipase A2- C22orf20 epsilon) (iPLA2-epsilon) Q9NRQ2 PLS4_HUMAN Phospholipid scramblase 4 (PL scramblase 4) (Ca(2+)-dependent phospholipid PLSCR4 GIG43 329 scramblase 4) (Cell growth-inhibiting gene 43 protein) (TRA1) P78562 PHEX_HUMAN Phosphate-regulating neutral endopeptidase (EC 3.4.24.—) (Metalloendopeptidase PHEX PEX 749 homolog PEX) (Vitamin D-resistant hypophosphatemic rickets protein) (X-linked hypophosphatemia protein) (HYP) O15162 PLS1_HUMAN Phospholipid scramblase 1 (PL scramblase 1) (Ca(2+)-dependent phospholipid PLSCR1 318 scramblase 1) (Erythrocyte phospholipid scramblase) (MmTRA1b) Q8NAT1 PMGT2_HUMAN Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGnT2) (EC POMGNT2 AGO61 580 2.4.1.—) (Extracellular O-linked N-acetylglucosamine transferase-like) C3orf39 EOGTL (Glycosyltransferase-like domain-containing protein 2) GTDC2 Q8IV08 PLD3_HUMAN Phospholipase D3 (PLD 3) (EC 3.1.4.4) (Choline phosphatase 3) (HindIII K4L homolog) PLD3 490 (Hu-K4) (Phosphatidylcholine-hydrolyzing phospholipase D3) Q9NRY6 PLS3_HUMAN Phospholipid scramblase 3 (PL scramblase 3) (Ca(2+)-dependent phospholipid PLSCR3 295 scramblase 3) Q9NRY7 PLS2_HUMAN Phospholipid scramblase 2 (PL scramblase 2) (Ca(2+)-dependent phospholipid PLSCR2 297 scramblase 2) Q96AD5 PLPL2_HUMAN Patatin-like phospholipase domain-containing protein 2 (EC 3.1.1.3) (Adipose triglyceride PNPLA2 ATGL 504 lipase) (Calcium-independent phospholipase A2) (Desnutrin) (IPLA2-zeta) (Pigment FP17548 epithelium-derived factor) (TTS2.2) (Transport-secretion protein 2) (TTS2) Q9BX97 PLVAP_HUMAN Plasmalemma vesicle-associated protein (Fenestrated endothelial-linked structure PLVAP FELS PV1 442 protein) (Plasmalemma vesicle protein 1) (PV-1) Q8WZA1 PMGT1_HUMAN Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGnTI) (EC POMGNT1 660 2.4.1.—) (UDP-GlcNAc: alpha-D-mannoside beta-1,2-N-acetylglucosaminyltransferase I.2) MGAT1.2 (GnT I.2) UNQ746/PRO1475 Q8TE99 PXYP1_HUMAN 2-phosphoxylose phosphatase 1 (EC 3.1.3.—) (Acid phosphatase-like protein 2) (Xylosyl PXYLP1 ACPL2 480 phosphatase) (epididymis luminal protein 124) HEL124 XYLP UNQ370/PRO706 Q8TC12 RDH11_HUMAN Retinol dehydrogenase 11 (EC 1.1.1.300) (Androgen-regulated short-chain RDH11 ARSDR1 318 dehydrogenase/reductase 1) (HCV core-binding protein HCBP12) (Prostate short-chain PSDR1 SDR7C1 dehydrogenase/reductase 1) (Retinal reductase 1) (RalR1) (Short chain CGI-82 dehydrogenase/reductase family 7C member 1) Q9Y644 RFNG_HUMAN Beta-1,3-N-acetylglucosaminyltransferase radical fringe (EC 2.4.1.222) (O-fucosylpeptide RFNG 331 3-beta-N-acetylglucosaminyltransferase) Q6AZY7 SCAR3_HUMAN Scavenger receptor class A member 3 (Cellular stress response gene protein) SCARA3 CSR 606 Q6ZMJ2 SCAR5_HUMAN Scavenger receptor class A member 5 (Scavenger receptor hIg) SCARA5 495 UNQ2938/PRO28700 P67812 SC11A_HUMAN Signal peptidase complex catalytic subunit SEC11A (EC 3.4.21.89) (Endopeptidase SEC11A SEC11L1 179 SP18) (Microsomal signal peptidase 18 kDa subunit) (SPase 18 kDa subunit) (SEC11 SPC18 SPCS4A homolog A) (SEC11-like protein 1) (SPC18) Q9BY50 SC11C_HUMAN Signal peptidase complex catalytic subunit SEC11C (EC 3.4.21.89) (Microsomal signal SEC11C SEC11L3 192 peptidase 21 kDa subunit) (SPase 21 kDa subunit) (SEC11 homolog C) (SEC11-like SPC21 SPCS4C protein 3) (SPC21) Q8IXA5 SACA3_HUMAN Sperm acrosome membrane-associated protein 3 (Cancer/testis antigen 54) (CT54) SPACA3 LYC3 215 (Lysozyme-like acrosomal sperm-specific secretory protein ALLP-17) (Lysozyme-like LYZL3 SLLP1 protein 3) (Sperm lysozyme-like protein 1) (Sperm protein reactive with antisperm SPRASA antibodies) (Sperm protein reactive with ASA) [Cleaved into: Sperm acrosome UNQ424/PRO862 membrane-associated protein 3, membrane form; Sperm acrosome membrane- associated protein 3, processed form] P0C7V7 SC11B_HUMAN Putative signal peptidase complex catalytic subunit SEC11B (EC 3.4.21.89) (SEC11 SEC11B SEC11L2 166 homolog B) (SEC11-like protein 2) SPCS4B Q9NSC7 SIA7A_HUMAN Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (EC 2.4.99.3) (GalNAc ST6GALNAC1 600 alpha-2,6-sialyltransferase I) (ST6GalNAc I) (ST6GalNAcI) (Sialyltransferase 7A) (SIAT7- SIAT7A A) UNQ543/PRO848 Q9H4F1 SIA7D_HUMAN Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6- ST6GALNAC4 302 sialyltransferase (EC 2.4.99.7) (NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc-alpha-2,6- SIAT3C SIAT7D sialyltransferase) (ST6GalNAc IV) (ST6GalNAcIV) (Sialyltransferase 3C) (SIAT3-C) (Sialyltransferase 7D) (SIAT7-D) Q92186 SIA8B_HUMAN Alpha-2,8-sialyltransferase 8B (EC 2.4.99.—) (Sialyltransferase 8B) (SIAT8-B) ST8SIA2 SIAT8B 375 (Sialyltransferase St8Sia II) (ST8SiaII) (Sialyltransferase X) (STX) STX P15907 SIAT1_HUMAN Beta-galactoside alpha-2,6-sialyltransferase 1 (Alpha 2,6-ST 1) (EC 2.4.99.1) (B-cell ST6GAL1 SIAT1 406 antigen CD75) (CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,6- sialyltransferase 1) (ST6Gal I) (ST6GalI) (Sialyltransferase 1) Q16585 SGCB_HUMAN Beta-sarcoglycan (Beta-SG) (43 kDa dystrophin-associated glycoprotein) (43DAG) (A3b) SGCB 318 Q13326 SGCG_HUMAN Gamma-sarcoglycan (Gamma-SG) (35 kDa dystrophin-associated glycoprotein) (35DAG) SGCG 291 Q96LD1 SGCZ_HUMAN Zeta-sarcoglycan (Zeta-SG) (ZSG1) SGCZ 299 Q92185 SIA8A_HUMAN Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (EC 2.4.99.8) (Alpha-2,8- ST8SIA1 SIAT8 356 sialyltransferase 8A) (Ganglioside GD3 synthase) (Ganglioside GT3 synthase) SIAT8A (Sialyltransferase 8A) (SIAT8-A) (Sialyltransferase St8Sia I) (ST8SiaI) Q92187 SIA8D_HUMAN CMP-N-acetylneuraminate-poly-alpha-2,8-sialyltransferase (EC 2.4.99.—) (Alpha-2,8- ST8SIA4 PST PST1 359 sialyltransferase 8D) (Polysialyltransferase-1) (Sialyltransferase 8D) (SIAT8-D) SIAT8D (Sialyltransferase St8Sia IV) (ST8SiaIV) P61647 SIA8F_HUMAN Alpha-2,8-sialyltransferase 8F (EC 2.4.99.—) (Sialyltransferase 8F) (SIAT8-F) ST8SIA6 SIAT8F 398 (Sialyltransferase St8Sia VI) (ST8SiaVI) Q96JF0 SIAT2_HUMAN Beta-galactoside alpha-2,6-sialyltransferase 2 (Alpha 2,6-ST 2) (EC 2.4.99.1) (CMP-N- ST6GAL2 KIAA1877 529 acetylneuraminate-beta-galactosamide-alpha-2,6-sialyltransferase 2) (ST6Gal II) SIAT2 (ST6GalII) (hST6Gal II) (Sialyltransferase 2) A6NLE4 SIM23_HUMAN Small integral membrane protein 23 SMIM23 C5orf50 156 Q07837 SLC31_HUMAN Neutral and basic amino acid transport protein rBAT (NBAT) (D2h) (Solute carrier family 3 SLC3A1 RBAT 685 member 1) (b(0, +)-type amino acid transport protein) O43173 SIA8C_HUMAN Sia-alpha-2,3-Gal-beta-1,4-GlcNAc-R: alpha 2,8-sialyltransferase (EC 2.4.99.—) (Alpha- ST8SIA3 SIAT8C 380 2,8-sialyltransferase 8C) (Alpha-2,8-sialyltransferase III) (ST8 alpha-N-acetyl- neuraminide alpha-2,8-sialyltransferase 3) (Sialyltransferase 8C) (SIAT8-C) (Sialyltransferase St8Sia III) (ST8SiaIII) Q11201 SIA4A_HUMAN CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (Alpha 2,3- ST3GAL1 SIAT4 340 ST 1) (Beta-galactoside alpha-2,3-sialyltransferase 1) (EC 2.4.99.4) (Gal-NAc6S) (Gal- SIAT4A beta-1,3-GalNAc-alpha-2,3-sialyltransferase) (SIATFL) (ST3Gal I) (ST3GalI) (ST3GalA.1) (ST3O) (Sialyltransferase 4A) (SIAT4-A) Q969X2 SIA7F_HUMAN Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 6 (EC 2.4.99.—) (GalNAc ST6GALNAC6 333 alpha-2,6-sialyltransferase VI) (ST6GalNAc VI) (ST6GalNAcVI) (hST6GalNAc VI) SIAT7F (Sialyltransferase 7F) (SIAT7-F) UNQ708/PRO1359 Q9UNP4 SIAT9_HUMAN Lactosylceramide alpha-2,3-sialyltransferase (EC 2.4.99.9) (CMP- ST3GAL5 SIAT9 418 NeuAc: lactosylceramide alpha-2,3-sialyltransferase) (Ganglioside GM3 synthase) UNQ2510/PRO5998 (STSGal V) (STSGalV) (Sialyltransferase 9) Q9H5K3 SG196_HUMAN Protein O-mannose kinase (POMK) (EC 2.7.1.183) (Protein kinase-like protein SgK196) POMK SGK196 350 (Sugen kinase 196) Q9Y274 SIA10_HUMAN Type 2 lactosamine alpha-2,3-sialyltransferase (EC 2.4.99.—) (CMP-NeuAc: beta- ST3GAL6 SIAT10 331 galactoside alpha-2,3-sialyltransferase VI) (ST3Gal VI) (ST3GalVI) (Sialyltransferase 10) Q16842 SIA4B_HUMAN CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (Alpha 2,3- ST3GAL2 SIAT4B 350 ST 2) (Beta-galactoside alpha-2,3-sialyltransferase 2) (EC 2.4.99.4) (Gal-NAc6S) (Gal- beta-1,3-GalNAc-alpha-2,3-sialyltransferase) (ST3Gal II) (ST3GalII) (ST3GalA.2) (Sialyltransferase 4B) (SIAT4-B) Q11206 SIA4C_HUMAN CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 4 (Alpha 2,3- ST3GAL4 CGS23 333 ST 4) (Beta-galactoside alpha-2,3-sialyltransferase 4) (EC 2.4.99.—) (Alpha 2,3- NANTA3 SIAT4C sialyltransferase IV) (Gal-NAc6S) (Gal-beta-1,4-GalNAc-alpha-2,3-sialyltransferase) STZ (SAT-3) (ST-4) (ST3Gal IV) (ST3GalIV) (ST3GalA.2) (STZ) (Sialyltransferase 4C) (SIAT4-C) Q9UJ37 SIA7B_HUMAN Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 2 (EC 2.4.99.—) (GalNAc ST6GALNAC2 374 alpha-2,6-sialyltransferase II) (ST6GalNAc II) (ST6GalNAcII) (SThM) (Sialyltransferase SIAT7B SIATL1 7B) (SIAT7-B) STHM Q9BVH7 SIA7E_HUMAN Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (EC 2.4.99.—) (GD1 alpha ST6GALNAC5 336 synthase) (GalNAc alpha-2,6-sialyltransferase V) (ST6GalNAc V) (ST6GalNAcV) SIAT7E (Sialyltransferase 7E) (SIAT7-E) Q11203 SIAT6_HUMAN CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (EC 2.4.99.6) ST3GAL3 SIAT6 375 (Beta-galactoside alpha-2,3-sialyltransferase 3) (Alpha 2,3-ST 3) (Gal beta-1,3(4) GlcNAc alpha-2,3 Sialyltransferase) (N-acetyllactosaminide alpha-2,3-sialyltransferase) (ST3Gal III) (STSGalIII) (ST3N) (Sialyltransferase 6) Q12884 SEPR_HUMAN Prolyl endopeptidase FAP (EC 3.4.21.26) (170 kDa melanoma membrane-bound FAP 760 gelatinase) (Dipeptidyl peptidase FAP) (EC 3.4.14.5) (Fibroblast activation protein alpha) (FAPalpha) (Gelatine degradation protease FAP) (EC 3.4.21.—) (Integral membrane serine protease) (Post-proline cleaving enzyme) (Serine integral membrane protease) (SIMP) (Surface-expressed protease) (Seprase) [Cleaved into: Antiplasmin-cleaving enzyme FAP, soluble form (APCE) (EC 3.4.14.5) (EC 3.4.21.—) (EC 3.4.21.26)] Q8NDV1 SIA7C_HUMAN Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (EC 2.4.99.—) (GalNAc ST6GALNAC3 305 alpha-2,6-sialyltransferase III) (ST6GalNAc III) (ST6GalNAcIII) (STY) (Sialyltransferase SIAT7C 7C) (SIAT7-C) UNQ2787/PRO7177 O15466 SIA8E_HUMAN Alpha-2,8-sialyltransferase 8E (EC 2.4.99.—) (Sialyltransferase 8E) (SIAT8-E) ST8SIA5 SIAT8E 376 (Sialyltransferase St8Sia V) (ST8SiaV) Q92629 SGCD_HUMAN Delta-sarcoglycan (Delta-SG) (35 kDa dystrophin-associated glycoprotein) (35DAG) SGCD 289 Q86WD7 SPA9_HUMAN Serpin A9 (Centerin) (Germinal center B-cell-expressed transcript 1 protein) SERPINA9 GCET1 417 SERPINA11 UNQ692/PRO1337 P61009 SPCS3_HUMAN Signal peptidase complex subunit 3 (EC 3.4.—.—) (Microsomal signal peptidase 22/23 kDa SPCS3 SPC22 180 subunit) (SPC22/23) (SPase 22/23 kDa subunit) UNQ1841/PRO3567 Q9UH99 SUN2_HUMAN SUN domain-containing protein 2 (Protein unc-84 homolog B) (Rab5-interacting protein) SUN2 FRIGG 717 (Rab5IP) (Sad1/unc-84 protein-like 2) KIAA0668 RAB5IP UNC84B Q9Y5Y6 ST14_HUMAN Suppressor of tumorigenicity 14 protein (EC 3.4.21.109) (Matriptase) (Membrane-type ST14 PRSS14 855 serine protease 1) (MT-SP1) (Prostamin) (Serine protease 14) (Serine protease TADG- SNC19 TADG15 15) (Tumor-associated differentially-expressed gene 15 protein) P14410 SUIS_HUMAN Sucrase-isomaltase, intestinal [Cleaved into: Sucrase (EC 3.2.1.48); Isomaltase (EC SI 1827 3.2.1.10)] O94901 SUN1_HUMAN SUN domain-containing protein 1 (Protein unc-84 homolog A) (Sad1/unc-84 protein-like SUN1 KIAA0810 812 1) UNC84A Q9NUM4 T106B_HUMAN Transmembrane protein 106B TMEM106B 274 Q9H7V2 SYNG1_HUMAN Synapse differentiation-inducing gene protein 1 (SynDIG1) (Dispanin subfamily C SYNDIG1 C20orf39 258 member 2) (DSPC2) (Transmembrane protein 90B) TMEM90B P02786 TFR1_HUMAN Transferrin receptor protein 1 (TR) (TfR) (TfR1) (Trfr) (T9) (p90) (CD antigen CD71) TFRC 760 [Cleaved into: Transferrin receptor protein 1, serum form (sTfR)] Q9UP52 TFR2_HUMAN Transferrin receptor protein 2 (TfR2) TFR2 801 Q9NRS4 TMPS4_HUMAN Transmembrane protease serine 4 (EC 3.4.21.—) (Channel-activating protease 2) TMPRSS4 437 (CAPH2) (Membrane-type serine protease 2) (MT-SP2) TMPRSS3 UNQ776/PRO1570 P50591 TNF10_HUMAN Tumor necrosis factor ligand superfamily member 10 (Apo-2 ligand) (Apo-2L) (TNF- TNFSF10 APO2L 281 related apoptosis-inducing ligand) (Protein TRAIL) (CD antigen CD253) TRAIL O43508 TNF12_HUMAN Tumor necrosis factor ligand superfamily member 12 (APO3 ligand) (TNF-related weak TNFSF12 APO3L 249 inducer of apoptosis) (TWEAK) [Cleaved into: Tumor necrosis factor ligand superfamily DR3LG member 12, membrane form; Tumor necrosis factor ligand superfamily member 12, UNQ181/PRO207 secreted form] Q06643 TNFC_HUMAN Lymphotoxin-beta (LT-beta) (Tumor necrosis factor C) (TNF-C) (Tumor necrosis factor LTB TNFC TNFSF3 244 ligand superfamily member 3) P41273 TNFL9_HUMAN Tumor necrosis factor ligand superfamily member 9 (4-1BB ligand) (4-1BBL) TNFSF9 254 Q6ZMR5 TM11A_HUMAN Transmembrane protease serine 11A (EC 3.4.21.—) (Airway trypsin-like protease 1) TMPRSS11A 421 (Epidermal type-II transmembrane serine protease) (Esophageal cancer-susceptibility ECRG1 HATL1 gene 1 protein) HESP Q6ZWK6 TM11F_HUMAN Transmembrane protease serine 11F (EC 3.4.21.—) (Airway trypsin-like protease 4) TMPRSS11F HATL4 438 P23510 TNFL4_HUMAN Tumor necrosis factor ligand superfamily member 4 (Glycoprotein Gp34) (OX40 ligand) TNFSF4 TXGP1 183 (OX40L) (TAX transcriptionally-activated glycoprotein 1) (CD antigen CD252) P01375 TNFA_HUMAN Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily TNF TNFA TNFSF2 233 member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form] O15393 TMPS2_HUMAN Transmembrane protease serine 2 (EC 3.4.21.—) (Serine protease 10) [Cleaved into: TMPRSS2 PRSS10 492 Transmembrane protease serine 2 non-catalytic chain; Transmembrane protease serine 2 catalytic chain] Q9H3S3 TMPS5_HUMAN Transmembrane protease serine 5 (EC 3.4.21.—) (Spinesin) TMPRSS5 457 Q7RTY8 TMPS7_HUMAN Transmembrane protease serine 7 (EC 3.4.21.—) (Matriptase-3) TMPRSS7 843 O43557 TNF14_HUMAN Tumor necrosis factor ligand superfamily member 14 (Herpes virus entry mediator ligand) TNFSF14 HVEML 240 (HVEM-L) (Herpesvirus entry mediator ligand) (CD antigen CD258) [Cleaved into: Tumor LIGHT necrosis factor ligand superfamily member 14, membrane form; Tumor necrosis factor UNQ391/PRO726 ligand superfamily member 14, soluble form] P48023 TNFL6_HUMAN Tumor necrosis factor ligand superfamily member 6 (Apoptosis antigen ligand) (APTL) FASLG APT1LG1 281 (CD95 ligand) (CD95-L) (Fas antigen ligand) (Fas ligand) (FasL) (CD antigen CD178) CD95L FASL [Cleaved into: Tumor necrosis factor ligand superfamily member 6, membrane form; TNFSF6 Tumor necrosis factor ligand superfamily member 6, soluble form (Receptor-binding FasL ectodomain) (Soluble Fas ligand) (sFasL); ADAM10-processed FasL form (APL); FasL intracellular domain (FasL ICD) (SPPL2A-processed FasL form) (SPA)] Q86T26 TM11B_HUMAN Transmembrane protease serine 11B (EC 3.4.21.—) (Airway trypsin-like protease 5) TMPRSS11B 416 HATL5 O95150 TNF15_HUMAN Tumor necrosis factor ligand superfamily member 15 (TNF ligand-related molecule 1) TNFSF15 TL1 VEGI 251 (Vascular endothelial cell growth inhibitor) [Cleaved into: Tumor necrosis factor ligand superfamily member 15, membrane form; Tumor necrosis factor ligand superfamily member 15, secreted form] Q9UL52 TM11E_HUMAN Transmembrane protease serine 11E (EC 3.4.21.—) (Serine protease DESC1) TMPRSS11E 423 (Transmembrane protease serine 11E2) [Cleaved into: Transmembrane protease serine DESC1 11E non-catalytic chain; Transmembrane protease serine 11E catalytic chain] TMPRSS11E2 UNQ742/PRO1461 Q8IU80 TMPS6_HUMAN Transmembrane protease serine 6 (EC 3.4.21.—) (Matriptase-2) TMPRSS6 811 UNQ354/PRO618 Q7Z410 TMPS9_HUMAN Transmembrane protease serine 9 (EC 3.4.21.—) (Polyserase-I) (Polyserine protease 1) TMPRSS9 1059 (Polyserase-1) [Cleaved into: Serase-1; Serase-2; Serase-3] Q9BYE2 TMPSD_HUMAN Transmembrane protease serine 13 (EC 3.4.21.—) (Membrane-type mosaic serine TMPRSS13 MSP 586 protease) (Mosaic serine protease) TMPRSS11 O14788 TNF11_HUMAN Tumor necrosis factor ligand superfamily member 11 (Osteoclast differentiation factor) TNFSF11 OPGL 317 (ODF) (Osteoprotegerin ligand) (OPGL) (Receptor activator of nuclear factor kappa-B RANKL TRANCE ligand) (RANKL) (TNF-related activation-induced cytokine) (TRANCE) (CD antigen CD254) [Cleaved into: Tumor necrosis factor ligand superfamily member 11, membrane form; Tumor necrosis factor ligand superfamily member 11, soluble form] O60507 TPST1_HUMAN Protein-tyrosine sulfotransferase 1 (EC 2.8.2.20) (Tyrosylprotein sulfotransferase 1) TPST1 370 (TPST-1) O60235 TM11D_HUMAN Transmembrane protease serine 11D (EC 3.4.21.—) (Airway trypsin-like protease) TMPRSS11D HAT 418 [Cleaved into: Transmembrane protease serine 11D non-catalytic chain; Transmembrane protease serine 11D catalytic chain] Q9Y2B1 TMEM5_HUMAN Transmembrane protein 5 TMEM5 443 P57727 TMPS3_HUMAN Transmembrane protease serine 3 (EC 3.4.21.—) (Serine protease TADG-12) (Tumor- TMPRSS3 ECHOS1 454 associated differentially-expressed gene 12 protein) TADG12 UNQ323/PRO382 Q9Y275 TN13B_HUMAN Tumor necrosis factor ligand superfamily member 13B (B lymphocyte stimulator) (BLyS) TNFSF13B BAFF 285 (B-cell-activating factor) (BAFF) (Dendritic cell-derived TNF-like molecule) (TNF- and BLYS TALL1 APOL-related leukocyte expressed ligand 1) (TALL-1) (CD antigen CD257) [Cleaved into: TNFSF20 ZTNF4 Tumor necrosis factor ligand superfamily member 13b, membrane form; Tumor necrosis UNQ401/PRO738 factor ligand superfamily member 13b, soluble form] P32971 TNFL8_HUMAN Tumor necrosis factor ligand superfamily member 8 (CD30 ligand) (CD30-L) (CD antigen TNFSF8 CD30L 234 CD153) CD30LG Q13061 TRDN_HUMAN Triadin TRDN 729 Q9UNG2 TNF18_HUMAN Tumor necrosis factor ligand superfamily member 18 (Activation-inducible TNF-related TNFSF18 AITRL 199 ligand) (AITRL) (Glucocorticoid-induced TNF-related ligand) (hGITRL) GITRL TL6 UNQ149/PRO175 Q9H2S6 TNMD_HUMAN Tenomodulin (TeM) (hTeM) (Chondromodulin-1-like protein) (ChM1L) (hChM1L) TNMD CHM1L 317 (Chondromodulin-I-like protein) (Myodulin) (Tendin) UNQ771/PRO1565 O60704 TPST2_HUMAN Protein-tyrosine sulfotransferase 2 (EC 2.8.2.20) (Tyrosylprotein sulfotransferase 2) TPST2 377 (TPST-2) Q9UKU6 TRHDE_HUMAN Thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE) (TRH-degrading TRHDE 1024 ectoenzyme) (EC 3.4.19.6) (Pyroglutamyl-peptidase II) (PAP-II) (TRH-specific UNQ2507/PRO5995 aminopeptidase) (Thyroliberinase) Q9Y2C2 UST_HUMAN Uronyl 2-sulfotransferase (EC 2.8.2.—) UST DS2ST 406 Q8NBZ7 UXS1_HUMAN UDP-glucuronic acid decarboxylase 1 (EC 4.1.1.35) (UDP-glucuronate decarboxylase 1) UXS1 420 (UGD) (UXS-1) UNQ2538/PRO6079 Q86Y38 XYLT1_HUMAN Xylosyltransferase 1 (EC 2.4.2.26) (Peptide O-xylosyltransferase 1) (Xylosyltransferase I) XYLT1 XT1 959 (XT-I) (XylT-I) P17861 XBP1_HUMAN X-box-binding protein 1 (XBP-1) (Tax-responsive element-binding protein 5) (TREB-5) XBP1 TREB5 XBP2 261 [Cleaved into: X-box-binding protein 1, cytoplasmic form; X-box-binding protein 1, luminal form] O75063 XYLK_HUMAN Glycosaminoglycan xylosylkinase (EC 2.7.1.—) (Xylose kinase) FAM20B KIAA0475 409 Q8NBI6 XXLT1_HUMAN Xyloside xylosyltransferase 1 (EC 2.4.2.n3) (UDP-xylose: alpha-xyloside alpha-1,3- XXYLT1 C3orf21 393 xylosyltransferase) PSEC0251 Q9H1B5 XYLT2_HUMAN Xylosyltransferase 2 (EC 2.4.2.26) (Peptide O-xylosyltransferase 1) (Xylosyltransferase XYLT2 XT2 865 II) (XT-II) (XylT-II) UNQ3058/PRO9878 A8MXE2 YI036_HUMAN Putative UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase LOC100288842 369 (EC 2.4.1.—) (Putative UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase LOC402377) (UDP-GlcNAc: betaGal beta-1,3-N-acetylglucosaminyltransferase 5 pseudogene) Q5STJ7 Q5STJ7_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALT4 378 hCG_17511 A0A090N7X6 A0A090N7X6_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT11 608 acetylgalactosaminyltransferase) hCG_1990637 tcag7.1057 Q5Q0U2 Q5Q0U2_HUMAN Fucosyltransferase 9 (EC 2.4.1.152) (Fucosyltransferase 9 (Alpha (1,3) FUT9 hCG_16703 359 fucosyltransferase), isoform CRA_a) (cDNA, FLJ95882, Homo sapiens fucosyltransferase 9 (alpha (1,3) fucosyltransferase) (FUT9), mRNA) A8K9Q8 A8K9Q8_HUMAN Hexosyltransferase (EC 2.4.1.—) hCG_2018639 384 A8K737 A8K737_HUMAN Fucosyltransferase (Fucosyltransferase 3 (Galactoside 3(4)-L-fucosyltransferase, Lewis FUT3 hCG_1645372 361 blood group)) (cDNA FLJ78078, highly similar to Human alpha (1,3/1,4) fucosyltransferase (FUT3)) G3V1S6 G3V1S6_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT2 533 acetylgalactosaminyltransferase) hCG_15927 Q58A54 Q58A54_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GalNAc-T18 607 acetylgalactosaminyltransferase) GALNT18 GALNTL4 hCG_1991780 A0A087WY64 A0A087WY64_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT2 92 A3KLL5 A3KLL5_HUMAN Sodium/potassium-transporting ATPase subunit beta ATP1B1 303 hCG_37798 Q2L4S5 Q2L4S5_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT19 598 acetylgalactosaminyltransferase) WBSCR17 hCG_19354 tcag7.519 B7ZKW0 B7ZKW0_HUMAN Sodium/potassium-transporting ATPase subunit beta ATP1B4 314 Q9P1W6 Q9P1W6_HUMAN Alpha-(1,3/1,4)-fucosyltransferase (cDNA, FLJ94139, highly similar to Homo sapiens FUT3 361 fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransferase, Lewis blood group included) (FUT3), mRNA) A0A024RC48 A0A024RC48_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT1 559 acetylgalactosaminyltransferase) hCG_2042960 D3DNF9 D3DNF9_HUMAN Sodium/potassium-transporting ATPase subunit beta ATP1B3 265 hCG_19938 A0A024RBT1 A0A024RBT1_HUMAN Hexosyltransferase (EC 2.4.1.—) hCG_2016450 378 D3DQI7 D3DQI7_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT10 506 acetylgalactosaminyltransferase) hCG_36809 B7Z5G5 B7Z5G5_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 527 acetylgalactosaminyltransferase) B5B9M4 B5B9M4_HUMAN Fucosyltransferase FUT3 361 Q68VJ8 Q68VJ8_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT16 GALNTL1 558 acetylgalactosaminyltransferase) hCG_21969 E7EVF0 E7EVF0_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 91 B2R8J0 B2R8J0_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 633 acetylgalactosaminyltransferase) C9J368 C9J368_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT5 50 B2RC53 B2RC53_HUMAN cDNA, FLJ95856, highly similar to Homo sapiens fucosyltransferase 11 (alpha (1,3) 492 fucosyltransferase) (FUT11), mRNA A8KAJ7 A8KAJ7_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 559 acetylgalactosaminyltransferase) Q8NHI0 Q8NHI0_HUMAN Hexosyltransferase (EC 2.4.1.—) 67 B4DIE4 B4DIE4_HUMAN Hexosyltransferase (EC 2.4.1.—) 91 B3KT16 B3KT16_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 372 acetylgalactosaminyltransferase) B7ZKV9 B7ZKV9_HUMAN Sodium/potassium-transporting ATPase subunit beta ATP1B4 322 Q6RC02 Q6RC02_HUMAN Hexosyltransferase (EC 2.4.1.—) 102 A0A087WV18 A0A087WV18_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP WBSCR17 519 acetylgalactosaminyltransferase) R4X5Z0 R4X5Z0_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 83 C9JGI4 C9JGI4_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT15 617 acetylgalactosaminyltransferase) Q24JS2 Q24JS2_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT6 622 acetylgalactosaminyltransferase) B7ZKV8 B7ZKV8_HUMAN Sodium/potassium-transporting ATPase subunit beta ATP1B4 357 I3L1V9 I3L1V9_HUMAN Sodium/potassium-transporting ATPase subunit beta (Fragment) ATP1B2 167 B4DLS4 B4DLS4_HUMAN cDNA FLJ55721, highly similar to Homo sapiens fucosyltransferase 10 (alpha (1,3) 521 fucosyltransferase) (FUT10), mRNA Q05BM8 Q05BM8_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT1 499 acetylgalactosaminyltransferase) A0A087X115 A0A087X115_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNTL6 417 acetylgalactosaminyltransferase) J3KNN1 J3KNN1_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT9 603 acetylgalactosaminyltransferase) B3KTQ4 B3KTQ4_HUMAN Hexosyltransferase (EC 2.4.1.—) 331 B3KY85 B3KY85_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 556 acetylgalactosaminyltransferase) E7EVS2 E7EVS2_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GALNT1 111 B7Z9S8 B7Z9S8_HUMAN Sodium/potassium-transporting ATPase subunit beta 247 B3W6H0 B3W6H0_HUMAN Fucosyltransferase FUT3 361 B3GVC1 B3GVC1_HUMAN Fucosyltransferase FUT3 361 Q8TDY1 Q8TDY1_HUMAN Hexosyltransferase (EC 2.4.1.—) OK/KNS-cl.1 204 Q6P7E6 Q6P7E6_HUMAN Fucosyltransferase 6 (Alpha (1,3) fucosyltransferase) FUT6 359 F8VUJ3 F8VUJ3_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP POC1B-GALNT4 575 acetylgalactosaminyltransferase) B3KNV8 B3KNV8_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 607 acetylgalactosaminyltransferase) Q7L9G8 Q7L9G8_HUMAN Hexosyltransferase (EC 2.4.1.—) 331 Q6RC00 Q6RC00_HUMAN Hexosyltransferase (EC 2.4.1.—) 331 M0QX58 M0QX58_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT3 127 B4E056 B4E056_HUMAN cDNA FLJ56031, highly similar to Homo sapiens fucosyltransferase 10 (alpha (1,3) 529 fucosyltransferase) (FUT10), mRNA Q58A70 Q58A70_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GalNAc-T10 581 acetylgalactosaminyltransferase) B3KQP5 B3KQP5_HUMAN Hexosyltransferase (EC 2.4.1.—) 378 B3KRF8 B3KRF8_HUMAN Hexosyltransferase (EC 2.4.1.—) 378 Q6RBZ9 Q6RBZ9_HUMAN Hexosyltransferase (EC 2.4.1.—) 319 I3L3J8 I3L3J8_HUMAN Sodium/potassium-transporting ATPase subunit beta (Fragment) ATP1B2 172 D7UNW5 D7UNW5_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT6 622 acetylgalactosaminyltransferase) Q49AT3 Q49AT3_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 331 B4DL56 B4DL56_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 603 acetylgalactosaminyltransferase) Q6RC01 Q6RC01_HUMAN Hexosyltransferase (EC 2.4.1.—) 144 B3KP58 B3KP58_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 460 acetylgalactosaminyltransferase) E9PJ79 E9PJ79_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT6 121 B2R7V3 B2R7V3_HUMAN cDNA, FLJ93618, highly similar to Homo sapiens fucosyltransferase 6 (alpha (1,3) 359 fucosyltransferase) (FUT6), mRNA C9J0F8 C9J0F8_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GALNT1 65 E5D8G0 E5D8G0_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 601 acetylgalactosaminyltransferase) B3KQT5 B3KQT5_HUMAN Hexosyltransferase (EC 2.4.1.—) 372 C9J5K2 C9J5K2_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT5 81 C9J8U7 C9J8U7_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GALNT1 54 H0YAH3 H0YAH3_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GALNT7 454 acetylgalactosaminyltransferase) (Fragment) C9JD16 C9JD16_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GALNT1 58 B7Z6K2 B7Z6K2_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 533 acetylgalactosaminyltransferase) B7Z5C5 B7Z5C5_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP 517 acetylgalactosaminyltransferase) Q58A53 Q58A53_HUMAN Polypeptide N-acetylgalactosaminyltransferase (EC 2.4.1.—) (Protein-UDP GalNAc-T17 598 acetylgalactosaminyltransferase) C9IYY0 C9IYY0_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT5 62 A6NGH2 A6NGH2_HUMAN Sodium/potassium-transporting ATPase subunit beta 295 V9GYR2 V9GYR2_HUMAN Sodium/potassium-transporting ATPase subunit beta (Fragment) ATP1B1 130 K7ENC0 K7ENC0_HUMAN Alpha-(1,3)-fucosyltransferase 5 FUT5 374 R4X604 R4X604_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 151 Q8NFN0 Q8NFN0_HUMAN Hexosyltransferase (EC 2.4.1.—) 181 Q58I18 Q58I18_HUMAN Sodium/potassium-transporting ATPase subunit beta (Fragment) ATP1B3 137 R4X601 R4X601_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 208 Q499Z2 Q499Z2_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GALT6 304 Q6LEU2 Q6LEU2_HUMAN Sodium/potassium-transporting ATPase subunit beta (Fragment) ATP1B1 303 A0A0A0MS93 A0A0A0MS93_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALT5 314 R4X5Z4 R4X5Z4_HUMAN Hexosyltransferase (EC 2.4.1.—) B3GALNT1 331 Q53F50 Q53F50_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) 331 M0R199 M0R199_HUMAN Hexosyltransferase (EC 2.4.1.—) (Fragment) B3GNT3 250

Table of Sequences in Appended Sequence Listing SEQ ID NO: Illustrative Description 1 DNA sequence of chimeric protein - comprising the extracellular domain of PD-1, followed by the hinge-CH2—CH3 domain of human IgG4 and short linker, followed by the extracellular domain of OX40L. 2 Amino acid sequence of chimeric protein - comprising the extracellular domain of PD-1, followed by the hinge-CH2—CH3 domain of human IgG4 and short linker, followed by the extracellular domain of OX40L. 3 Codon-optimized nucleic acid sequence, which is optimized for expression by Chinese Hamster (CHO) cells 4 DNA sequence encoding the extracellular domain of PD-1-Fc-the extracellular domain of TL1A 5 Amino acid sequence encoded by a codon optimized nucleotide sequence of SEQ ID NO: 4 6 Nucleotide sequence of construct (ex: A fusion protein encoding the extracellular domain of BTLA, linked through an Fc to OX40L) 7 Amino acid sequence encoded by nucleotide sequence of SEQ ID NO: 6 8 DNA sequence of a fusion protein incorporating the extracellular domain of TIGIT, linked via an Fc linker to OX40L 9 Amino acid sequence encoded by a codon optimized nucleotide sequence of SEQ ID NO: 8 10 DNA sequence of a fusion protein incorporating the extracellular domain of TIM3, linked through an Fc region to human OX40L 11 Amino acid sequence encoded by a codon optimized nucleotide sequence of SEQ ID NO: 10 12 Nucleotide sequence of the extracellular domain of CD172a adjoined with an Fc linker sequence to the extracellular domain of human OX40L 13 Amino acid sequence encoded by a codon optimized nucleotide sequence of SEQ ID NO: 12 14 Nucleotide sequence of the extracellular domain of TMIGD2 adjoined with an Fc linker sequence to the extracellular domain of human OX40L 15 Amino acid sequence encoded by a codon optimized nucleotide sequence of SEQ ID NO: 14 16 mRNA sequence of human OX40L 17 Amino acid sequence of human OX40L 18 Nucleic acid sequence of the hinge-CH2—CH3 Sequence from human IgG1 19 cDNA sequence of human PD-1 20 Nucleic acid sequence of human PD-1-Fc-OX40L codon optimized for expression by Chinese Hamster (CHO) cells 21 Nucleic acid sequence of human PD-1-Fc-OX40L 22 Amino acid sequence of SL-279252 23 Amino acid sequence of Linker 24 Amino acid sequence of Linker 25 Amino acid sequence of Linker 26 Amino acid sequence of Linker 27 Amino acid sequence of Linker 28 Amino acid sequence of Linker 29 Amino acid sequence of Linker 30 Amino acid sequence of Linker 31 Amino acid sequence of Linker 32 Amino acid sequence of CD279 33 Amino acid sequence of CD172a 34 Amino acid sequence of BTLA 35 Amino acid sequence of TIGIT 36 Amino acid sequence of TIM3 37 Amino acid sequence of CD200 38 Amino acid sequence of TMIGD2 39 Amino acid sequence of VISTA 40 Amino acid sequence of VSIG8 41 Amino acid sequence of BTNL2 42 Amino acid sequence of TNFRSF1b 43 Amino acid sequence of CD276 44 Amino acid sequence of CD244 45 Amino acid sequence of LAG3 46 Amino acid sequence of CSF1R 47 Amino acid sequence of TGFBR1 48 Amino acid sequence of IL-10R 49 Amino acid sequence of CD40 50 Amino acid sequence of OX40 51 Amino acid sequence of 41BB 52 Amino acid sequence of CTLA4 53 Amino acid sequence of PD-L1 54 Amino acid sequence of PD-L2 55 Amino acid sequence of B7-H4 56 Amino acid sequence of OX40L 57 Amino acid sequence of GITRL 58 Amino acid sequence of 41BBL 59 Amino acid sequence of TL1A 60 Amino acid sequence of CD40L 61 Amino acid sequence of CD30L 62 Amino acid sequence of TRAIL 63 Amino acid sequence of CD70 64 blank 65 blank 66 blank 67 blank 68 blank 69 blank 70 Amino acid sequence of Linker - IgG4 hinge-CH2—CH3 71 Amino acid sequence of Linker - IgG4 hinge-CH2—CH3 S228P 72 Amino acid sequence of Linker - IgG4 hinge-CH2-CD3 S228P FcRn 73 Amino acid sequence of Joining Linker 74 Amino acid sequence of Joining Linker 75 Amino acid sequence of Joining Linker 76 Amino acid sequence of Joining Linker 77 Amino acid sequence of Joining Linker 78 Amino acid sequence of Joining Linker

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 32, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 33, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 34, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 35, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 36, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 37, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 38, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 39, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 40, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 41, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 42, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 43, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 44, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 45, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 46, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 47, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 48, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 49, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 50, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 51, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 52, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 53, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 54, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises: (i) the amino acid sequence of SEQ ID NO: 55, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and (ii) one of the amino acid sequences of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, and, optionally (iii) an Ig linker selected from the amino acid sequences of SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto, where, also optionally, one or more of (i) and (ii) are connected to (iii) via (iv) a joining linker of SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, or variants thereof. In various embodiments, the linkers (iii) or (iv) can be substituted for the amino acid sequence of SEQ ID NOs: 23-31, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 2, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 5, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 7, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 9, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 11, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 13, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 15, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

In some embodiments, the present chimeric protein comprises the amino acid sequence of SEQ ID NO: 22, or at least 90%, or 93%, or 95%, or 97%, or 98%, or 99% identity thereto.

EQUIVALENTS

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

All patents and publications referenced herein are hereby incorporated by reference in their entireties.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. 

What is claimed is:
 1. A heterologous chimeric protein comprising: (a) a first domain comprising a portion of PD-1 that is capable of binding a PD-1 ligand, (b) a second domain comprising a portion of OX-40 ligand (OX40L) that is capable of binding an OX-40L receptor, and (c) a linker linking the first domain and the second domain and comprising a hinge-CH2-CH3 Fc domain.
 2. The heterologous chimeric protein of claim 1, wherein the first domain comprises substantially all of the extracellular domain of PD-1 and the second domain comprises substantially all of the extracellular domain of OX40L.
 3. The heterologous chimeric protein of claim 1, wherein the heterologous chimeric protein is capable of inhibiting an immunosuppressive signal.
 4. The heterologous chimeric protein of claim 1, wherein the heterologous chimeric protein is capable of: (a) reducing or eliminating an immune inhibitory signal when the portion of PD-1 is bound to its ligand and/or (b) increasing or activating an immune stimulatory signal when the portion of OX40L is bound to its receptor.
 5. The heterologous chimeric protein of claim 1, wherein the PD-1 ligand is PD-L1.
 6. The heterologous chimeric protein of claim 1, wherein the OX-40L receptor is OX40.
 7. The heterologous chimeric protein of claim 1, wherein the heterologous chimeric protein is capable of simultaneously binding the PD-1 ligand and the OX-40L receptor, wherein the PD-1 ligand is PD-L1 and the OX-40L receptor is OX40.
 8. The heterologous chimeric protein of claim 1, wherein the heterologous chimeric protein is capable of increasing or preventing a decrease in a sub-population of CD4+ and/or CD8+ T cells.
 9. The heterologous chimeric protein of claim 1, wherein the heterologous chimeric protein is capable of enhancing tumor killing activity by T cells.
 10. The heterologous chimeric protein of claim 1, wherein the heterologous chimeric protein is capable of providing a sustained immunomodulatory effect.
 11. The heterologous chimeric protein of claim 1, wherein the linker comprises hinge-CH2-CH3 Fc domain derived from IgG4.
 12. The heterologous chimeric protein of claim 11, wherein the hinge-CH2-CH3 Fc domain is derived from human IgG4.
 13. The heterologous chimeric protein of claim 1, wherein the chimeric protein is expressed by a mammalian host cell as a secretable and functional single polypeptide chain.
 14. The heterologous chimeric protein of claim 1, wherein the portion of PD-1 comprises the amino acid sequence of SEQ ID NO:
 32. 15. The heterologous chimeric protein of claim 1, wherein the portion of OX40L comprises the amino acid sequence of SEQ ID NO:
 56. 16. The heterologous chimeric protein of claim 1, wherein the linker comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 71 or SEQ ID NO:
 72. 17. The heterologous chimeric protein of claim 1, wherein (a) the first domain comprises the amino acid sequence of SEQ ID NO: 32, (b) the second domain comprises the amino acid sequence of SEQ ID NO: 56, and (c) the linker comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:
 72. 18. An expression vector, comprising a nucleic acid encoding the heterologous chimeric protein of claim
 1. 19. A host cell, comprising the expression vector of claim
 18. 20. A pharmaceutical composition, comprising a therapeutically effective amount of the heterologous chimeric protein of claim
 1. 21. A recombinant fusion protein comprising: (a) a first domain comprising a portion of PD-1 comprising the amino acid sequence of SEQ ID NO: 32 and is capable of binding a PD-1 ligand, (b) a second domain comprising a portion of OX-40 ligand (OX40L) comprising the amino acid sequence of SEQ ID NO: 56 and is capable of binding an OX-40L receptor, and (c) a linker linking the first domain and the second domain and comprising a hinge-CH2-CH3 Fc domain.
 22. The recombinant fusion protein of claim 21, wherein the linker comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:
 72. 23. The recombinant fusion protein of claim 21, wherein the heterologous fusion protein is capable of simultaneously binding the PD-1 ligand and the OX-40L receptor, wherein the PD-1 ligand is PD-L1 and the OX-40L receptor is OX40. 